Clinical Trial Results:
Randomized, Double-Blind, Phase 3B Trial to Evaluate the Safety and Efficacy of 2 Treatment Regimens of Aztreonam 75 mg Powder and Solvent for Nebulizer Solution / Aztreonam for Inhalation Solution (AZLI) in Pediatric Subjects with Cystic Fibrosis (CF) and New Onset Respiratory Tract Pseudomonas aeruginosa (PA) Infection/Colonization
Summary
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EudraCT number |
2016-002749-42 |
Trial protocol |
BE GB IE AT FR DE ES NL IT GR DK Outside EU/EEA |
Global end of trial date |
23 Sep 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
18 Mar 2022
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First version publication date |
18 Mar 2022
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
GS-US-205-1850
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03219164 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Gilead Sciences
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Sponsor organisation address |
333 Lakeside Drive, Foster City, CA, United States, 94404
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Public contact |
Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
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Scientific contact |
Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000827-PIP01-09 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
23 Sep 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
27 May 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Sep 2021
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
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.
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Protection of trial subjects |
The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
28 Nov 2017
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
26 Months | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Austria: 7
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Country: Number of subjects enrolled |
Belgium: 3
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Country: Number of subjects enrolled |
Denmark: 9
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Country: Number of subjects enrolled |
France: 11
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Country: Number of subjects enrolled |
Germany: 7
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Country: Number of subjects enrolled |
Greece: 4
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Country: Number of subjects enrolled |
Israel: 8
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Country: Number of subjects enrolled |
Italy: 12
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Country: Number of subjects enrolled |
Netherlands: 3
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Country: Number of subjects enrolled |
Spain: 20
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Country: Number of subjects enrolled |
United Kingdom: 33
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Country: Number of subjects enrolled |
United States: 32
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Worldwide total number of subjects |
149
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EEA total number of subjects |
76
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
30
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Children (2-11 years) |
85
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Adolescents (12-17 years) |
34
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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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
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Screening details |
149 participants were screened. | |||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | |||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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AZLI 14 Days + Placebo 14 Days | |||||||||||||||||||||||||||||||||
Arm description |
75 milligrams per milliliter (mg/ml) of aztreonam was administered thrice daily (TID) for 14 days followed by placebo to match (PTM) aztreonam TID for 14 days, both aztreonam and PTM aztreonam were delivered via the PARI Altera® Nebulizer System. Participants below 2 years received aztreonam for inhalation solution (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. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
AZLI
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Investigational medicinal product code |
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Other name |
Cayston®, Aztreonam
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Pharmaceutical forms |
Powder and solvent for nebuliser solution
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Routes of administration |
Inhalation use
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Dosage and administration details |
75 mg/ml administered thrice daily.
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Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solvent for nebuliser solution
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Routes of administration |
Inhalation use
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Dosage and administration details |
Administered thrice daily.
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Arm title
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AZLI 28 Days | |||||||||||||||||||||||||||||||||
Arm description |
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. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
AZLI
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Investigational medicinal product code |
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Other name |
Cayston®, Aztreonam
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Pharmaceutical forms |
Powder and solvent for nebuliser solution
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Routes of administration |
Inhalation use
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Dosage and administration details |
75 mg/ml administered thrice daily.
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Baseline characteristics reporting groups
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Reporting group title |
AZLI 14 Days + Placebo 14 Days
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Reporting group description |
75 milligrams per milliliter (mg/ml) of aztreonam was administered thrice daily (TID) for 14 days followed by placebo to match (PTM) aztreonam TID for 14 days, both aztreonam and PTM aztreonam were delivered via the PARI Altera® Nebulizer System. Participants below 2 years received aztreonam for inhalation solution (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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AZLI 28 Days
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Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
AZLI 14 Days + Placebo 14 Days
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Reporting group description |
75 milligrams per milliliter (mg/ml) of aztreonam was administered thrice daily (TID) for 14 days followed by placebo to match (PTM) aztreonam TID for 14 days, both aztreonam and PTM aztreonam were delivered via the PARI Altera® Nebulizer System. Participants below 2 years received aztreonam for inhalation solution (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. | ||
Reporting group title |
AZLI 28 Days
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Reporting group description |
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. | ||
Subject analysis set title |
Tobramycin Nebulizer Solution (TNS)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The TNS group included historical data for the percentage of participants with PA-negative cultures during 28 days post-treatment period pooled from the published results from the studies conducted on the participants with new onset of PA infection and similar TNS treatment duration and follow-up.
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End point title |
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 | ||||||||||||
End point description |
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.
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End point type |
Primary
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End point timeframe |
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)
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Statistical analysis title |
AZLI 14 Days + Placebo 14 Days vs AZLI 28 Days | ||||||||||||
Comparison groups |
AZLI 14 Days + Placebo 14 Days v AZLI 28 Days
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Number of subjects included in analysis |
139
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||
Method |
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Parameter type |
Difference in percentage | ||||||||||||
Point estimate |
-8
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
-24.6 | ||||||||||||
upper limit |
8.6 | ||||||||||||
Notes [1] - Non-inferiority of the 14-day treatment regimen was claimed if the lower bound of 1-sided 97.5% confidence limit of the treatment difference (14-day course group vs 28-day course group) was above the noninferiority margin of -20%. |
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End point title |
Time From Primary Eradication to PA Recurrence Over a 108-Week Post-Treatment Follow-up Period | ||||||||||||
End point description |
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. Participants in the Evaluable Analysis Set were analyzed. 9999=Not Available as the calculated percentiles of event rate were not reached.
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End point type |
Secondary
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End point timeframe |
Last dose date of AZLI up to Week 112
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No statistical analyses for this end point |
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End point title |
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) [2] | ||||||||||||
End point description |
The historical data for the percentage of participants with PA-negative cultures during 28 days post-treatment period was pooled from the published results from the studies conducted on the participants with new onset of PA infection and similar TNS treatment duration and follow-up. AZLI 14 Day treatment group: Evaluable Analysis Set; TNS group: Participants with PA-negative cultures during 28 days post-treatment period whose historical data were pooled from published results from studies conducted on the participants with new onset of PA infection and similar TNS treatment duration and follow-up.
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End point type |
Secondary
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End point timeframe |
28 days post treatment (Weeks 4 to 6 for the 14 Day treatment group)
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Notes [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The data was reported for AZLI 14 Day group and for the TNS group historical data pooled from the published results from the studies conducted on the participants with new onset of PA infection and similar TNS treatment duration and follow-up was reported. |
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No statistical analyses for this end point |
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End point title |
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 | ||||||||||||
End point description |
ELITE study (NCT00391976): Participants with CF who had early PA infection received TNS. ELITE Study Matching Analysis Set=Participants from Evaluable Analysis set who satisfied published criteria for efficacy analysis population:
- Participants must be ≥ 6 months at randomization, no history of positive (+) anti-PA antibody (no anti-PA IgG antibody interpretation at Screening/Baseline) on record
- Did not use anti-pseudomonal antibiotics and PA negative (-) through 28 days after completion of treatment, within 2 years of Screening
- Non-missing PA culture result at 28 days after AZLI last dose
- No protocol deviation from study drug administration compliance and documented new onset of + respiratory tract culture for PA within 30 days of Screening [as either first lifetime documented PA+ culture/PA recovered after at least a 2-year history of PA- respiratory cultures (at least 2 cultures/year)]
9999=Not Available as the calculated percentiles of event rate were not reached.
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End point type |
Secondary
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End point timeframe |
Last dose date of AZLI up to Week 112
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse Events: First dose date up to 28 days plus 30 days;
All-Cause Mortality: Randomization up to 112 weeks
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Adverse event reporting additional description |
Adverse Events: Safety Analysis Set included participants who were randomized and received at least one dose of study drug.
All-Cause Mortality: Intent-To-Treat Analysis Set included all participants who were randomized in the study.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.1
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Reporting groups
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Reporting group title |
AZLI 14 Days Placebo 14 Days
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Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AZLI 28 Days
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Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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31 Mar 2017 |
• All computed tomography (CT) scan assessments were removed
• Exploratory objectives and endpoints related to CT scans were removed
• Clarified that all retreatment options listed in the protocol were non-exclusive
• Clarified that spirometry was only to be performed on participants who can reliably perform spirometry assessments
• Clarified that clinical observation should also be performed pre-and poststudy drug administration for participants 6 years of age and older who can’t reliably perform spirometry assessments
• Removed collection of body weight, height and vital signs after baseline, with the exception of unscheduled visits
• Removed all nasal swabs assessments after Day 1
• Eligibility criteria clarified as needed
• Corrected the follow-up culture phase schedule to specify that the first visit will occur at Week 16 and then every twelve weeks after that
• Removed hematology and serum chemistry samples from Baseline (if results are available within the last 12 months) and from the follow-up culture phase
• Clarified that participants must switch IP kits at Day 15. |
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06 Nov 2017 |
• The number of study centres were increased from 75 to 85 to mitigate risk of slow recruitment
• Exclusion criterion was amended so that antibiotics such as azithromycin were allowable in 7 days prior to Screening
• Respiratory sample collection methods expanded
• Biomarker sections updated to allow PA-specific antibody titre blood draw to be avoided if results were available within 24 months
• Change made to prohibited concomitant medication section to clarify that concurrent use of oral antipseudomonal antibiotics for a respiratory event was prohibited from Screening to Day 28
• Spirometry sections updated to clarify that percentage of forced expiratory volume (FEV1%) predicted was reported at all visits and was calculated by site
• Clarification throughout study procedure section as to what types of AEs/SAEs were reported at each visit
• Medical History section updated to clarify that the participant`s PA infection history, including the number of previous PA infections,
number of cultures taken and sampling methods in the previous 2 years were also recorded. |
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15 Apr 2020 |
• Clarification on how the missing PA culture data was evaluated
• Documentation of which personnel wiould be blinded/unblinded throughout the study
• Clarification that 130 evaluable participants were required for the efficacy analyses
• Unblinding of Gilead personnel was required for the primary analysis
• Confirmed that respiratory samples collected outside of the study as standard of care may be sent to local laboratory
• Local lab culture data may be used for analysis purposes
• The Biofire testing panel would be used for microbiological assessment of the nasal swabs. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
None reported |