Clinical trial NCT03158116
Conditions: Tracheostomy Infection
Keywords: tracheostomy tube Pseudomonas aeruginosa
Sponsor: UCSF Benioff Children's Hospital Oakland
Start date: 2017-07-01; Completion date: 2020-02-20
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a prospective, case-control clinical trial using inhaled Aztreonam (AZLI) in pediatric patients with a tracheostomy tube colonized with Pseudomonas aeruginosa. The aim of the study is to see if AZLI being taken in a one month on / one month off cycle over the course of a year can decrease the need for systemic antibiotics and/or hospitalizations.

Detailed description:
Inhalation aztreonam (AZLI) is an aerosolized formulation of the monobactam antibiotic aztreonam with lysine as a synthetic substance in place of arginine. This substitution was made as arginine, which is in the intravenous (IV) formulation of aztreonam, can cause airway inflammation as seen in patients with cystic fibrosis when aerosolized. There have been several published studies on the efficacy and adverse effects of aerosolized aztreonam in CF patients. Two placebo-controlled studies of AZLI revealed a benefit in patients with CF and colonization with PsA. AIR-CF1 revealed that a 28-day course of AZLI given three times daily (TID) resulted in improved respiratory symptoms. They measured this improvement by using a cystic fibrosis questionnaire (CFQ-R), measuring forced expiratory volume in 1 second (FEV 1), and measuring bacterial density in sputum. AIR-CF2 demonstrated that a 28-day course of AZLI followed by a 28-day course of Tobramycin Inhaled Solution (TIS) delayed the time to the need for additional inhaled or systemic anti-pseudomonal antibiotics. They also used the CFQ-R and measured FEV1 and found improvement in both when compared to placebo. In AIR-CF3, an open-label 18-month study was conducted to evaluate the efficacy of AZLI using a month on/month off cycle, and to observe long-term effects of the drug. This protocol found that AZLI did have a long-term suppressive effect on PsA as there was a persistent reduction in Pseudomonas CFUs from baseline each month of the study. As expected, the decreases in bacterial density were consistently occurring during on months; and during off months, the density increased toward baseline. Thrice-daily dosing appeared more efficacious than twice-daily dosing. This was attributed to the mode of action of aztreonam, as bacterial killing is dependent on time above the MIC (minimal inhibitory concentration). Adverse events include: cough, respiratory tract congestion, pharyngolaryngeal pain, nasal congestion, dyspnea, hemoptysis, rhinorrhea, wheezing, chest discomfort, crackles lung, pulmonary function testing decreased, non-cardiac chest pain, sinus congestion, sinus headache, dyspnea exacerbated, exertional dyspnea.

Antibiotics currently on the market as inhaled antibiotics include tobramycin (TOBI), polymyxin E (Colistin), and aztreonam (Cayston). Studies of all of these have shown clinical benefits in those with Cystic Fibrosis. Given these findings, there is a growing interest in the use of inhaled antibiotics in other disease processes in which subjects become colonized with bacteria in the lower respiratory tract.

The investigators propose a two-center, prospective, case control clinical trial on the use of inhaled aztreonam (AZLI) in pediatric patients ages 7-21 years with a tracheostomy who have had one of their previous 3 tracheostomy aspirate cultures positive for PsA. Their past history in the previous year of requirement for systemic antibiotics will be used for each subject as the historical control. A tracheostomy aspirate culture will be collected upon initiation of the study. The investigators will subsequently start the participants on AZLI on a one month on/one month off schedule. Tracheal aspirate cultures will continue to be collected quarterly (every 3 months), and the bacterial density will be used for analysis. Goal is to see if there is a decrease need for systemic antibiotics for PsA infection.

Arms: arm 1: All participants will be receiving the study drug
Interventions: intervention 1: Inhaled Aztreonam
Intervention descriptions: intervention 1: Inhaled antibiotic with anti-pseudomonal properties

Protocol documents:
Prot_SAP_000.pdf: 
A-PACT: The use of Inhaled Aztreonam to eliminate or decrease the bacterial burden of Pseudomonas 
Aeruginosa in Children with a Tracheostomy tube.  
 
NCT03158116 
 
Document Date 1/22/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


A-PACT: The use of Inhaled Aztreonam to eliminate or decrease the bacterial burden of Pseudomonas 
Aeruginosa in Children with a Tracheostomy tube.  
 
A study to determine if the aerosolized Anti-pseudomonal agent, inhaled Aztreonam, can eliminate or at 
least decrease the bacterial burden of Pseudomonas aeruginosa in children with a tracheostomy tube. 
 
ABSTRACT 
 
A. SPECIFIC AIMS 
B. BACKGROUND AND SIGNIFICANCE 
C. PRELIMINARY STUDIES/PROGRESS REPORTS 
D. RESEARCH DESIGN AND METHODS 
• 
Formulations 
• 
Dose, Administration, Duration, and Storage 
• 
Dosage Modification 
• 
Concomitant Therapy 
• 
Schedule of Assessments 
• 
Data Safety Monitoring Committee (DSMC) 
• 
Treatment Discontinuation 
• 
Follow Up Period 
• 
Compliance with Laws and Regulations 
• 
Institutional Review Board Approval 
• 
Study Protocol 
• 
Tracheostomy tube aspirate culture collection protocol 
  D1. Study Population 
  D2. Population Description 
  D3. Inclusion/Exclusion Criteria 
• 
Inclusion Criteria 
• 
Exclusion Criteria 
  D4. Drop-Out Criteria/Treatment Failure 
• 
Drop Out 
• 
Treatment Failure 
  D5. Sample Size/Power 
  D6. Statistical analysis 
• 
Randomization 
• 
Masking 
• 
Analysis 
• 
Drop Out/Treatment Failure Status 
  D7. Data Entry/Management 
  D8. Research Time Line 
  D9. Study Design 
• 
Training of Study Personnel 
• 
Identification and Recruitment of Subjects 
• 
Study Period-Hospital Admission 
  D10. Preparation of Manuscript 
E. HUMAN SUBJECTS RESEARCH 
 
E1. Recruitment and Informed Consent 
 
E2. Assessment of Safety 


E2.1 Methods For Eliciting, Recording and Assessing Adverse Events 
• 
Eliciting Adverse Events 
• 
Recording Adverse Events 
• 
Assessing Causality (Trial Drug Relationship to Adverse Event) 
E2.2 MedWatch 3500 Completion Methods 
E2.3 MedWatch 3500 Follow-up Information Methods 
E2.4.1 General Reporting of Serious Adverse Events Associated with Cayston 
E3. Risks/Benefits of Participation 
Appendix 
References 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Abstract: 
 
Children with a tracheostomy tube represent a complex group of children that rely on an artificial medical 
device to help them meet their oxygenation and ventilation needs. The tube may be required to overcome 
upper airway obstruction and/or for long-term mechanical ventilation.1,2 There is significant morbidity and 
mortality in children with a tracheostomy tube, the most common being pneumonia.3 Pseudomonas 
aeruginosa (PsA) is a common culprit. This bacteria is difficult to treat, and when a patient has a respiratory 
infection and is colonized with Pseudomonas, it requires prolonged use of systemic antibiotics, often 
intravenous and potentially a hospital admission.4–8 This leads to a higher cost to society in the number of 
school days missed by the child and in addition, the number of work days missed by the care provider.3  
Society is constantly attempting to reduce healthcare costs. One such attempt is the use of inhaled 
aztreonam to eliminate or at least decrease the bacterial load of PsA in children with a tracheostomy tube, 
thereby decreasing the future need for enteral or intravenous antibiotic use and/or hospitalization if the 
child has a respiratory illness.  There are currently no published studies on the use of inhaled antibiotics in 
children with a tracheostomy tube. Therefore, this proposal has been designed to build upon the anecdotal 
literature, by studying the efficacy of inhaled aztreonam to decrease the need for systemic (intravenous or 
enteral) antibiotics for respiratory infections in patients with a tracheostomy tube over a 12-month period. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


A. SPECIFIC AIMS 
 
The primary objective of this proposal is to determine in a longitudinal multi-center trial with historical 
controls whether inhaled aztreonam will decrease the frequency of respiratory infections requiring 
treatment with systemic antibiotics  (IV and enteral) in subjects with a tracheostomy tube over a 12 
month period.  
 
Secondary Aims:  
1) To determine if inhaled aztreonam can eliminate the colonization or at least decrease the bacterial 
density of Pseudomonas aeruginosa in patients with a tracheostomy tube who are colonized with 
Pseudomonas. 
2) To determine if there is a difference in eradication or decrease in bacterial load of Pseudomonas in 
those who have a Bivona vs. a Shiley tracheostomy tube. 
3) To determine if there is a decreased number of hospital admissions 
4) To determine if there is a shorter duration of hospital stays during the study period  
 
 
B. BACKGROUND AND SIGNIFICANCE 
 
Tracheostomies became widely used in the treatment of diphtheria in children in the 19th century. It was 
later used in the early 1950s during the poliomyelitis epidemic.1 There are several reasons that a 
tracheotomy is performed: need for long-term mechanical ventilation, upper airway obstruction (from 
airways malacia, vocal cord paralysis, subglottic stenosis, external compression), brain injury or CNS 
disorder leading to inability to cough up own secretions, severe head and/or neck trauma that obstructs 
breathing, and emergent situations when an endotracheal tube (ETT) cannot be placed successfully to 
ventilate a patient.9 There is significant morbidity and mortality in patients with a tracheostomy tube. In 
2014, a retrospective cohort analysis of the Healthcare Cost and Utilization Project (HCUP) Kid’s Inpatient 
Database (KID) 2009 was conducted. KID is a multistate database of 3.4 million hospital discharges from 
4,121 hospitals in 44 states. The most common organ system affected in children with a tracheostomy 
tube-necessitating hospital admission was the respiratory system (50.8%, n = 10,946), and they also 
accounted for the largest percentage of hospital charges (45.7%, $652 million U.S.).  Therefore, a better 
understanding of pneumonia prevention and management in children with a tracheostomy would be 
beneficial.3 
 
Bacterial colonization of the tracheobronchial tree almost always follows placement of a tracheostomy 
tube.10  Due to ineffective mucociliary transport and cough mechanisms that occur in patients with a 
tracheostomy, clearing of microorganisms from the upper airway becomes impaired, and thus, bacteria 
tend to colonize their airways.4 Gram negative bacterial colonization is common. This is due in part to the 
fact that children who are chronically ill and/or hospitalized with recurrent lower airway infections may 
have increased amounts of polymorphonuclear cells (PMNs). The PMNs have an enzyme, salivary elastase, 
that degrades fibronectin, which plays a role in protecting the airway epithelia from being colonized by 
gram negative bacteria.5 Most patients with a tracheostomy, if not all of them, become colonized with 
Pseudomonas aeruginosa (PsA), a gram negative rod, soon after placement of the tracheostomy.6  A 
recently published study found that PsA was the most commonly isolated bacteria in tracheostomy tube 
aspirate cultures in the pediatric population.11 
 
PsA is an opportunistic pathogen. Once infection is established, it is highly virulent, therefore it is difficult 
to eradicate.7  PsA exists as a biofilm, which is an organized matrix of bacterial colonies. In a study 


published in 2002, it was found that there was no difference in susceptibility to biofilm formation among 
four different tracheostomy tube materials tested: polyvinyl chloride (Mallinckrodt; St. Louis), silicone 
(Bivona Medical Technologies; Gary Ind.), stainless steel (Pilling Weck; Marckham, Ont.), sterling silver 
(Pilling Weck).12 The role of mechanical ventilation in the development of tracheal colonization is still 
unclear. In the study published in1984, persistent enteric gram negative bacterial (EGNB) tracheal 
colonization developed in 4 subjects receiving mechanical ventilation, 2 others treated with mechanical 
ventilation did not become colonized. In addition, 3 subjects developed persistent EGNB tracheal 
colonization while not being treated with mechanical ventilation.8  Few studies have been done to look at 
this.  
 
When treating patients with tracheostomy tubes with antibiotics, most clinicians treat “empirically”. The 
most frequent antibiotics prescribed are trimethoprim-sulfamethoxazole and amoxicillin-clavulanate; only 
a few use inhaled antibiotics. Of those that treat with inhaled antibiotics, they use inhaled tobramycin and 
inhaled gentamycin.4 However, there is no literature to date that supports the use of inhaled antibiotics in 
children with tracheostomy tubes.  
 
Nebulized antibiotics have the benefit that they can be delivered directly into the airways, therefore, they 
target the site of infection.  As such, they are unlikely to cause adverse side effects due to minimal systemic 
absorption.13 In addition, nebulized antibiotics provide sputum concentrations well above the minimum 
inhibitory concentrations (MICs) necessary (about 10 times the MIC) to allow penetration of antibiotics into 
biofilms, and therefore achieve a bactericidal effect. When using intravenous antibiotics, there are higher 
risks of systemic toxicity as higher drug doses are needed to reach the appropriate MIC.4,14 
 
Antibiotics have been trialed as an inhaled formulation since the 1940s. However, prior to the late 1990s, 
these antibiotics were the aerosolized antibiotics designed for parenteral administration. These 
formulations caused significant bronchial irritation due to added preservatives and non-physiologic 
chemical composition.11 In the late 1990s, inhaled antibiotics were just being studied for the use in cystic 
fibrosis (CF) patients with chronic endobronchial colonization with PsA.  In 1998, tobramycin inhaled 
solution (TIS) was the first antibiotic to be developed and approved for use as an aerosolized antibiotic in 
patients with CF.15  Multiple clinical trials have been conducted in those with CF assessing the efficacy of 
inhaled antibiotics. They commonly compared inhalation of an aminoglycoside such as gentamycin or 
tobramycin or other anti-pseudomonas antibiotics with normal, hypertonic, or hypotonic saline as 
placebo.7  
 
A study published in 1999 in the New England Journal of Medicine suggested the clinical efficacy of inhaled 
tobramycin given intermittently (28 days on, and 28 days off). It revealed when compared to placebo that 
inhaled tobramycin was safe, improved lung function, decreased sputum PsA density, and lowered the risk 
of hospitalization and intravenous anti-pseudomonal antibiotic use.   The administration of tobramycin in 
these trials (28 days on drug, 28 days off drug) was used to reduce the emergence of tobramycin 
resistance.16 Another study by the same group found no evidence of increased selection for intrinsically 
tobramycin-resistant bacterial pathogens.17 
 
A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis patients with bronchiectasis 
chronically infected with a variety of pathogens was conducted over a 1-year period and was published in 
2011. 65 subjects were randomized to receive twice-daily nebulized gentamicin (80mg) or twice daily 
nebulized 0.9% saline, 5ml.  They found that regular, long-term nebulized gentamicin significantly reduces 
the bacterial density and airways inflammation, with less sputum purulence. In the total cohort who 


received nebulized gentamicin, 21.9% vs. 6% in the saline group reported bronchospasm. No nephrotoxicity 
or ototoxicity was detected.13 
 
Inhalation aztreonam (AZLI) is an aerosolized formulation of the monobactam antibiotic aztreonam with 
lysine as a synthetic substance in place of arginine.  This substitution was made as arginine, which is in the 
intravenous (IV) formulation of aztreonam, can cause airway inflammation as seen in patients with cystic 
fibrosis when aerosolized.18,19  There have been several published studies on the efficacy and adverse 
effects of aerosolized aztreonam in CF patients. Two placebo-controlled studies of AZLI revealed a benefit 
in patients with CF and colonization with PsA. AIR-CF1 revealed that a 28-day course of AZLI given three 
times daily (TID) resulted in improved respiratory symptoms. They measured this improvement by using a 
cystic fibrosis questionnaire (CFQ-R), measuring forced expiratory volume in 1 second (FEV 1), and 
measuring bacterial density in sputum. AIR-CF2 demonstrated that a 28-day course of AZLI followed by a 
28-day course of Tobramycin Inhaled Solution (TIS) delayed the time to the need for additional inhaled or 
systemic anti-pseudomonal antibiotics. They also used the CFQ-R and measured FEV1 and found 
improvement in both when compared to placebo. In AIR-CF3, an open-label 18-month study was 
conducted to evaluate the efficacy of AZLI using a month on/month off cycle, and to observe long-term 
effects of the drug.  This protocol found that AZLI did have a long-term suppressive effect on PsA as there 
was a persistent reduction in Pseudomonas CFUs from baseline each month of the study.  As expected, the 
decreases in bacterial density were consistently occurring during on months; and during off months, the 
density increased toward baseline. Thrice-daily dosing appeared more efficacious than twice-daily dosing. 
This was attributed to the mode of action of aztreonam, as bacterial killing is dependent on time above the 
MIC (minimal inhibitory concentration).  Adverse events include: cough, respiratory tract congestion, 
pharyngolaryngeal pain, nasal congestion, dyspnea, hemoptysis, rhinorrhea, wheezing, chest discomfort, 
crackles lung, pulmonary function testing decreased, non-cardiac chest pain, sinus congestion, sinus 
headache, dyspnea exacerbated, exertional dyspnea.19 
 
Antibiotics currently on the market as inhaled antibiotics include tobramycin (TOBI), polymyxin E (Colistin), 
and aztreonam (Cayston).  Studies of all of these have shown clinical benefits in those with Cystic Fibrosis. 
Given these findings, there is a growing interest in the use of inhaled antibiotics in other disease processes 
in which subjects become colonized with bacteria in the lower respiratory tract.  
 
We propose a multi-center longitudinal study with historical controls on the use of inhaled aztreonam 
(AZLI) in pediatric patients ages 7-21 years with a tracheostomy who, in the last year, have had one of their 
previous 3 tracheostomy aspirate cultures positive for PsA.  Their past history if the previous year of 
requirement for systemic antibiotics will be used for each subject as the historical control. A tracheostomy 
aspirate culture will be collected upon initiation of the study. We will subsequently start them on AZLI on a 
one month on/one month off schedule. Tracheal aspirate cultures will continue to be collected quarterly 
(every 3 months), and the bacterial density will be used for analysis. Goal is to see if there is a decrease 
need for systemic antibiotics for PsA infection. 
 
In addition, we will also be simultaneously performing a retrospective chart review of all patients at UCSF 
Benioff Children's Hospital Oakland age 0-21 years with a tracheostomy tube to find out the incidence of 
Pseudomonas acquisition, and their subsequent need for systemic antibiotics and hospitalization.  This will 
give us prevalence data for our population that will help with statistical analysis of the above proposed 
study. 
 
C. PRELIMINARY STUDIES/PROGRESS REPORTS 
None 


 
D. RESEARCH DESIGN AND METHODS 
• 
Formulations 
o Lyophilized aztreonam = AZLI (75mg/vial) 
o Diluent (0.17% sodium chloride): 1 mL/ampule 
• 
Dose, Administration, Duration, and Storage 
o Administer one dose (one single use vial and one ampule of diluent) 3 times a day for 28 
days 
o Use dose immediately after reconstitution 
o Administer only with the Altera® Nebulizer System and a compressor. Do not administer 
with any other type of nebulizer 
o AZLI will be stored in room temperature 
• 
Dosage Modification 
o The dose will not be modified in this study 
• 
Concomitant Therapy 
o There is no concomitant therapy that will be given with our study, but the subjects can 
continue any other therapy they are receiving as determined by their treating physician.  If 
there are any concomitant medications administered to the subjects, it will be recorded on 
concomitant medication log form by study staff on the Data Collection sheet (see Appendix 
3). 
• 
Schedule of Assessments 
o Patients are to be assessed every 3 months. A questionnaire will be filled out by the parent 
or legal guardian regarding concomitant medications and side effects.  Please see detailed 
Study Protocol section on the next page for details.  
• 
Data Safety Monitoring Committee (DSMC) 
o A DSMC will be formed to monitor subjects’ safety during this study. This committee will be 
a central committee based here at UBCHO. They will review data from the 2 sites involved 
in the study. 
o In order to avoid spending alpha, no interim analysis for efficacy will be performed. 
However, the DSMC will review the unblended data after the first 6 months of data 
subjects have completed the study for an analysis of safety. They will determine if there is 
an absolute difference between study groups for the following criteria: days in the ICU, 
oxygen requirement, and serious adverse events. They will also be responsible for 
reviewing any adverse event in an unblended fashion as it occurs. If a difference is found, a 
sequential analysis will be performed to determine if there is a significant difference 
(p<0.01 for the first 3 criteria; p<0.05 for SAE). If the DSMC determines on sequential 
analysis that a significant difference exists, the DSMC will be required to notify the PI, who 
in turn will be required to stop the study and notify the IRBs, FDA, and Gilead. 
• 
Treatment Discontinuation 
o Study medication will be discontinued in subjects that develop respiratory failure (defined 
as: 1) pCO2 >60 mmHg; 2) oxygen requirement > 5 L/min; and 3) Invasive or non-invasive 
ventilation) and/or worsening of their clinical status (such as refractory coughing) during 
the trial. These subjects will then be categorized as treatment failures. 
• 
Follow Up Period 
o Each subject will go back to their respective institutions and their physicians are to decide if 
they wish to keep the subject on the inhaled aztreonam.  At 3 and 6 months, we will obtain 


data on number of exacerbations requiring systemic antibiotics as well as tracheostomy 
aspirate cultures if one was obtained (culture result, CFUs, MIC, and sensitivities).  
• 
Compliance with Laws and Regulations 
o This study will be conducted in accordance with current Good Clinical Practices (GCPs). The 
Declaration of Helsinki, and local ethical and legal requirements.  
• 
Institutional Review Board Approval 
o Institutional Review Board (IRB) approval will be obtained prior to the start of this study at 
all 3 institutions (UCSF Benioff Children’s Hospital Oakland and Children’s Hospital Central 
California). 
o A copy of each institution’s IRB approval of this study will be sent to Gilead. The Principal 
Investigator at each institution is responsible for keeping the IRB apprised of the progress 
of the study and of any changes made to the protocol as deemed appropriate. The Principal 
Investigator at each institution must also keep the IRB informed of any significant adverse 
events. 
• 
Study Protocol: 
o Recruitment: 
§ 
Each institution’s designated PI will query their respective institutions’ pulmonary 
and ENT group patient panels who have a tracheostomy tube.  (For UBCHO, we will 
only use the pulmonary group’s patients as all tracheostomy patients at this 
institution are followed by pulmonary as of 11/30/15 and Rachna Wadia will be 
calling them.  She will be performing a retrospective review that has been 
approved by the UBCHO IRB # 2016-015. Using this review, she will be able to 
identify UBCHO patients that meet criteria to be recruited in the A-PACT study). 
§ 
If they have had a culture positive for Pseudomonas aeruginosa, then each 
respective institution’s designated research coordinator will call the patient’s 
family to recruit them.  We will also put out a flyer to recruit patients in each 
institution that is involved in this study (UCSF Benioff Children’s Hospital Oakland, 
Lucile Packard Children’s Hospital at Stanford, and Children’s Hospital Central 
California). 
§ 
We will recruit all subjects ages 7-21 years old with a tracheostomy tube and a 
history of Pseudomonas in one of their tracheostomy tube cultures in the past 
year. Patient will then be scheduled for an appointment in their respective 
institution’s CTSI or pulmonary/ENT clinic for enrollment.  
 
o Enrollment:  
§ 
Eligibility Checklist (see Appendix 3 – Eligibility Checklist) 
• 
Consent/Assent  
• 
Inclusion/Exclusion Criteria 
§ 
Demographic Data (see Appendix 4- Demographic Sheet) 
• 
Past Medical History 
• 
Family History 
• 
Social History 
§ 
Data Collection (see Appendix 5 – Data Collection) 
• 
Physical exam 
• 
Tracheostomy tube information (type, size, cuffed, etc.) 
§ 
Document most recent culture.  If + for PsA in the past month, then can start 
participant on study drug (see Visit 1).  


• 
If has not had a culture in the past month, then obtain a tracheostomy 
aspirate culture using standardized sterile technique amongst all 
institutions involved in the study (See Appendix 10 – Obtaining a 
tracheostomy aspirate culture) 
• 
Once culture results obtained and positive for Pseudomonas aeruginosa, 
the participant will be called to schedule their Visit 1 Study visit 
§ 
Patient’s chart will be reviewed in the previous year. Data collected will include 
tracheostomy aspirate culture results, number of respiratory illnesses requiring 
systemic antibiotics and/or hospitalization, duration of antibiotic treatment, and 
duration of hospitalizations.  We will also collect the date they first acquired 
Pseudomonas aeruginosa as seen on a tracheostomy tube aspirate culture. 
 
o Visit 1: 
§ 
Data Collection (see Appendix – 5) 
• 
Physical exam 
• 
Tracheostomy tube information (type, size, cuffed, etc.) 
• 
Study Medication history (return of used vials, currently taking study med?) 
• 
Systemic Antibiotics and Hospitalization: 
o Has the participant  
§ 
received systemic antibiotics in last 3 months? 
§ 
Had a respiratory infection in last 3 months? 
§ 
Been hospitalized in the last 3 months? 
§ 
Obtain tracheostomy aspirate culture using standardized sterile technique amongst 
all institutions involved in the study (See Appendix 10 – Obtaining a tracheostomy 
aspirate culture) 
• 
Tracheostomy tube cultures will be routinely collected quarterly (every 3 
months) starting with the first culture on day of enrollment (total of 5 
cultures for each subject).  The culture sample will be obtained with a new 
sterile suction catheter.  The specimens will be cultured for aerobic 
bacteria. Bacterial load/density will be performed on each culture.  
§ 
The patient will then receive the first dose AZLI via e-flow nebulizer system. When 
giving the first dose of inhaled antibiotics, caution is warranted for bronchospasm. 
Therefore, it is recommended that the first dose be given while supervised.  If they 
develop audible wheezing on exam, or they have a decrease in oxyhemoglobin 
desaturation of 3% or more, then they are considered to have bronchospasm.  If 
the subject fails according to the above criteria, then they should receive albuterol 
(4 puffs via MDI and spacer or 1 nebulizer treatment 2.5mg will be administered). If 
they return to baseline within 15 minutes, then they will need to take albuterol 
prior to administration of inhaled antibiotic.   If they do not return to baseline, or if 
they have any other adverse event that leads to an allergic reaction, then they will 
be taken out of the study. 
§ 
Parent/guardian will be taught how to administer the study drug using the e-flow 
nebulizer system. 
§ 
They will then be sent home with the study drug to be taken 3x daily on a 28 day 
on / 28 day off cycle starting the day after Study Visit 1 and wills start on the ON 
cycle. 
 


o Study Visits #2-5: 
§ 
Data Collection (see Appendix – 5) 
• 
Physical exam 
• 
Tracheostomy tube information (type, size, cuffed, etc.) 
• 
Study Medication history (return of used vials = adherence, currently taking 
study med?) 
o Adherence: Patients are to return the empty vials, and this can be 
compared to the number of vials prescribed on their quarterly 
visits for when they have to come in and have a tracheostomy 
aspirate culture.  
§ 
Each site study coordinator will also call the subjects 
monthly to ask if they are taking their medication 
consistently and they are cycling on and off at the 
appropriate times. 
• 
Systemic Antibiotics and Hospitalization: 
o Has the participant  
§ 
received systemic antibiotics in last 3 months? 
§ 
Had a respiratory infection in last 3 months? 
§ 
Been hospitalized in the last 3 months? 
§ 
Document last tracheostomy tube aspirate culture on the culture results form 
(Appendix 6).  
§ 
Adverse events Form filled out by participant’s guardian or participant if they are 
18 years of age and capable of filling out the form (See Appendix 7a) 
• 
Symptoms include: cough, respiratory tract congestion, pharyngolaryngeal 
pain, nasal congestion, dyspnea, hemoptysis, rhinorrhea, wheezing, chest 
discomfort, crackles lung, pulmonary function testing decreased, non-
cardiac chest pain, sinus congestion, sinus headache, dyspnea exacerbated, 
and exertional dyspnea.   
§ 
Adverse Events Reporting Form filled out by Study Staff if participant or guardian 
reports an adverse event (See Appendix 7b).  If an adverse event is reported, the 
MEDWATCH form must be filled out and sent to the FDA (see Appendix 7c).  
§ 
Obtain tracheostomy aspirate culture using standardized sterile technique amongst 
all institutions involved in the study (See Appendix 10 – Obtaining a tracheostomy 
aspirate culture) 
§ 
They will then be sent home with the study drug to be taken 3x daily to continue 
on a 28 day on / 28 day off cycle. 
§ 
On Visit 5: the Termination of Study Participation Form will be filled out (See 
Appendix 8). This form is to be filled out at the last study visit to verify the 
participant has completed the study and on what date. Or, it is to be used if 
the parent/guardian or participant if 18 years or older has withdrawn consent 
and why.  The date of withdrawal will be documented on this sheet. 
o Follow-up: 
§ 
At 3 and 6 months, each institution’s PI or research coordinator at (UCSF Benioff 
Children’s Hospital Oakland, Lucile Packard Children’s Hospital at Stanford, and 
Children’s Hospital Central California) will call the participant’s primary 
pulmonologist/ENT physician to obtain follow-up information regarding whether or 
not the participant continued on the study drug, how many respiratory 
exacerbations have they had requiring systemic antibiotics and/or hospitalizations, 


and tracheostomy aspirate culture results if there are any that were done. (See 
Appendix 9).  
• 
**If the subject is hospitalized during the study period, the subject may continue on the study drug 
as planned. However, this decision will be left to the subject’s primary physician. This study will not 
interfere with the standard of care. If the study drug is discontinued during the hospitalization, 
then they can restart it where they left off once discharged (example: admitted while on day 11 of 
an “On” month. Day after discharge will be day 12 of the same “On” month.  If this were to occur, 
the Study Drug Break form will be filled out (Appendix 11).  
 
 
 
  D1. Study Population 
Subjects ages 7-21 years old with a tracheostomy tube who have grown Pseudomonas aeruginosa in a 
tracheostomy tube culture in the previous 3 cultures performed. 
 
  D2. Population Description 
The population eligible will be children who have undergone a tracheotomy in the Bay Area, California at 
one of the following Children’s hospitals: UCSF Benioff Children’s Hospital Oakland and Valley Children’s 
Hospital in Madera, California. This population includes, but is not limited to: Caucasians, Hispanics, Native 
Americans, Asians, and Africans. Caucasian subjects are defined as being of the white race and having 
parents and grandparents not born in Mexico, other Central/South American or Caribbean countries, Spain 
and /or Portugal. Non-Caucasian subjects are defined as self-reporting at least one non-Caucasian parent.   
 
  D3. Inclusion/Exclusion Criteria 
• 
Inclusion Criteria 
o Age: 7 – 21 years old 
o Currently has a tracheostomy tube 
o One of previous 3 tracheostomy tube aspirate cultures positive for Pseudomonas 
aeruginosa 
o Non-smoker 
o Ability of parent to provide informed consent, as evidenced by signing a copy of the 
consent form approved by the Institutional Review Board of the subject’s respective study 
institution. 
o Written assent for children 7-17 years of age.  
o Informed consent for children ages 18-21, as evidence by signing a copy of the consent 
form approved by the Institutional Review Board of the subject’s respective study 
institution. 
• 
Exclusion Criteria 
o History of immunodeficiency 
o History of cystic fibrosis. Primary ciliary dyskinesia, or bronchiectasis 
o History of tuberculosis 
o History of positive culture for Burkholderia cepacia  
o Use of inhaled antibiotics in the last 6 months 
   
D4. Drop-Out Criteria/Treatment Failure 
• 
Drop Out 
o When a subject or legal guardian withdraws consent, data collection will stop and the 
subject will be dropped from the experiment. However, all efforts will be made to have the 


subject or legal guardian allow study staff to continue to follow the subjects as this will 
allow for a more intent-to-treat basis.  
• 
Treatment Failure 
o When a subject experiences adverse effect of treatment, the study medication will be 
stopped. However, the subject will continue to be followed and data collected as described 
as all subjects will be analyzed on an intent-to-treat basis.  
 
  D5. Sample Size/Power 
Due to the paucity of studies performed on children with a tracheostomy tube, it is difficult to perform a 
sample size calculation. Our study is a pilot study. Depending on the number of patients at the institutions 
participating in this study, we plan to recruit about 10-15 subjects. 
 
 D6. Statistical analysis 
• 
Randomization 
o There will be no randomization. All subjects will receive the study drug. 
• 
Masking 
o All subjects will be receiving the inhaled antibiotic (AZLI), so there will not be any blinding. 
• 
Analysis 
o Standard techniques for the analysis of the data from longitudinal trials with historical 
controls will be applied. Initial bivariate comparisons using a t-test for continuous data and 
a chi-square test for categorical comparing the 2 groups.  Then, using a longitudinal model 
for each outcome measure comparing the 2 groups over time while adjusting for 
demographic characteristics, such as age. 
o We will use the software program STATA to perform data analysis. 
• 
Drop Out/Treatment Failure Status 
o Initial analysis of the data will be completed using an intention-to-treat-model. Therefore, 
the available data from all randomized subjects will be included in the statistical analyses, 
regardless of drop out/treatment failure status. Supplemental statistical analyses will be 
applied in which data collected after the assignment of treatment failure status are 
excluded. 
 
  D7. Data Entry/Management 
 
Data entry and quality control checks will be performed. The data will be kept in an electronic 
database with access limited by password protection. Hard copy and electronic data will be stored in a 
locked area accessible only to authorized personnel. Electronic data will be backed-up daily on zip disk and 
stored in a locked cabinet in a separate room. 
 
  D8. Research Time Line 
 
The proposed research should take 20 months to complete + 6 month follow-up period. The first 
month will be used to train study personnel in the study design. The next 3 months will be used for subject 
recruitment and data collection. Goal is to have subjects on the study drug or placebo for a total of 12 
months. There will then be a 6 month follow-up period. The remaining months will be used for completion 
of the data analysis and manuscript preparation. 
 
The start of the subject recruitment will be targeted for mid 2016 with a goal of enrollment of 10-15 
subjects. Completion of the study will then be late 2017 / early 2018. 
 
  D9. Study Design 


 The general tasks for the contact, interview, and study period will include the following: 
• 
Training of Study Personnel 
o All study personnel will pass the CITI course for human subjects’ research or its equivalent 
o All study personnel will undergo HIPAA training and certification 
o All study personnel will undergo training of the proper methods to obtain informed 
consent and assent. 
o All study personnel will receive training in how to obtain a tracheostomy aspirate culture 
using sterile techniques 
• 
Identification and Recruitment of Subjects 
o Ascertainment of potential subjects from each pulmonary center’s database 
o Interview subject and/or subject’s legal guardian regarding participation in clinical study by 
study personnel.  
o Obtain informed consent from the legal guardian of subjects aged 17 years and younger 
and either verbal or written informed assent of subject 
o Obtain informed consent from subjects aged 18-21 years 
• 
Study Period 
o Subjects will receive study drug three times a day via nebulized treatment for 1 year 
alternating 28 days on / 28 days off. 
o Collection of data for primary and secondary outcomes throughout the study period 
§ 
Respiratory Infection necessitating systemic antibiotics will be defined as meeting 3 
of the 6 following criteria: fever, hypoxemia (SpO2 < 92%), cough, increased 
tracheal secretions, change in color of secretions from clear and/or white, and 
radiographic evidence of pneumonia. 
§ 
If a study subject does have a respiratory infection necessitating systemic 
antibiotics, then they will have to visit their study coordinator to have a tracheal 
aspirate culture collected 
§ 
Tracheal aspirate cultures will be collected in a standardized way in all institutions 
participating in the study 
§ 
Laboratory culture techniques will be standardized in all institutions participating in 
the study 
 
  D10. Preparation of Manuscript 
After the completion of data collection, entry, and analysis, manuscript preparation shall be done. 
The completed manuscript will then be submitted to an appropriate publication and/or conference such as: 
Pediatrics, American Journal of Respiratory and Critical Care Medicine, and American Thoracic Society’s 
International Conference.  
 
E. HUMAN SUBJECTS RESEARCH 
 E1. Recruitment and Informed Consent 
• 
Trained study personnel will approach eligible subjects to participate in this proposal once they 
have been identified to have a tracheostomy tube and a tracheostomy aspirate culture positive for 
Pseudomonas. It will be stressed to the subjects and their legal guardians that their participation in 
this study is voluntary. They have the right to withdraw from the study at any time, and that 
choosing not to participate in the study will not adversely affect their medical care or their 
relationship with any of their medical care providers. Patients and their legal guardians will also be 
asked to sign an authorization for release of medical information. 
 E2. Assessment of Safety 


• 
The safety of AZLI will be assessed through the collection of both Adverse Events and Serious 
Adverse Events (SAEs) 
• 
All adverse events that occur during this study from the initiation of study drug administration until 
completion of the study, whether attributed to the study drug, that are observed by the 
Investigator, study staff, subject’s physician or reported by the patient and/or guardian will be 
recorded on an adverse event case report form. In addition to recording the adverse event, 
attributes of the adverse event will be recorded as well. These attributes will include a description, 
onset, and resolution date, duration, maximum severity, assessment of relationship to the study 
agent, other suspect agent(s), treatment procedures, and the patient’s pre-existing disease, action 
taken and outcome.  
o In the event of an adverse event, the first concern will be for the safety of the subject. 
Investigators are required to report to Gilead, IRB, and FDA any serious adverse event, 
whether expected or unexpected, and which is assessed by the investigator to be 
reasonably or possibly related to AZLI. All deaths, regardless of causality, will also be 
reported. All events meeting these criteria will be reported for the time period beginning 
with any amount of exposure to AZLI through the protocol-defined follow-up period. 
Serious criteria, definitions and guidance for reporting follow. 
• 
An Adverse Event (AE) is any untoward medical occurrence (e.g. sign, symptoms, disease, 
syndrome, intercurrent illness, abnormal lab finding) that emerges during AZLI treatment or is a 
pre-existing condition that worsens relative to the pretreatment state, regardless of the suspected 
cause.  
• 
Note: Unchanged, chronic conditions should not be recorded as an adverse event on the FDA safety 
and adverse event reporting program MedWatch unless there is an exacerbation of the chronic 
condition.  
• 
Serious Adverse Events (SAE) are adverse events occurring at any dose which meet one or more of 
the following serious criteria: 
o It resulted in death (i.e., the adverse event caused or led to death) 
o It was life threatening (i.e., the adverse event placed the patient at immediate risk of 
death: it does not apply to an adverse event that hypothetically might have caused death if 
it were more severe) 
o It required or prolonged inpatient hospitalization (i.e., the adverse event required any 
inpatient hospitalization or prolonged a hospitalization beyond the expected length of 
stay.) 
o It was disabling (i.e., the adverse event resulted in a substantial disruption of the patient’s 
ability to carry out normal life functions) 
o Is a congenital anomaly/birth defect (i.e., an adverse outcome in a child or fetus of a 
subject exposed to the trial drug prior to conception or during pregnancy) 
• 
Expected adverse events are those adverse events that are listed or characterized in the Package 
Insert or current Investigator Brochure 
• 
Unexpected adverse events are those not listed in the Package Insert (PI) or current Investigator 
Brochure (IB) or not identified. This includes adverse events for which the specificity or severity is 
not consistent with the description in the PI or IB. For example, under this definition, hepatic 
necrosis would be unexpected if the PI or IB only referred to elevated hepatic enzymes or hepatitis.  
 
  E2.1 Methods For Eliciting, Recording and Assessing Adverse Events 
• 
Eliciting Adverse Events 


o To elicit adverse events, simple questions with minimal connotations should be used as the 
initial questions at all evaluation points during the study.    
o A questionnaire (adverse events listed are those listed on the Package Insert of AZLI) will be 
given to the participant if they are 18 years old and capable, or to the guardian. (see 
Appendix 7b). 
• 
Recording Adverse Events 
o When completing a MedWatch form, investigators should consider the following when 
assigning a primary event term: 
§ 
Whenever possible, use recognized medical terms when recording adverse events 
on the adverse event section(s) of the MedWatch form. Do not use colloquialisms 
and/or abbreviations.  
§ 
If known, record the diagnosis (i.e., disease or syndrome) rather than component 
signs and symptoms on adverse event section(s) of the MedWatch (e.g., record 
congestive heart failure rather than dyspnea, rales, and cyanosis). However, signs 
and symptoms that are considered unrelated to an encountered syndrome or 
disease should be recorded as individual adverse events on the MedWatch (e.g., if 
congestive heart failure and gastrointestinal bleed are observed at the same time, 
each event should be recorded as an individual adverse event) 
§ 
Adverse events occurring secondary to other events (e.g., sequelae) should be 
identified by the primary cause. A “primary” adverse event, if clearly identifiable, 
generally represents the most accurate clinical term to record on adverse event 
pages of the MedWatch and the CRF. Events occurring secondary to the primary 
event should be described in the narrative description of the case. For example: 
• 
Orthostatic hypotension à fainting and fall to floor à head trauma à 
neck pain 
o The primary adverse event is orthostatic hypotension 
 
• 
Assessing Causality (Trial Drug Relationship to Adverse Event) 
o The investigator will determine which events are associated with the use of the trial drug. 
Investigators are required to report to Gilead any serious adverse event, whether expected 
or unexpected, and which is assessed by the investigator to be reasonably or possibly 
related to AZLI. All deaths, regardless of causality, will also be reported. All events meeting 
these criteria will be reported for the time period beginning with any amount of exposure 
to AZLI through the protocol-defined follow-up period. For reporting purposes, an AE 
should be regarded as related to or not related to the use of investigational product if the 
investigator believes: 
o Yes (includes possibly or probably) event is related to AZLI 
§ 
There is a clinically plausible time sequence between onset of the adverse event 
and AZLI administration; and/or 
§ 
There is a biologically plausible mechanism for AZLI causing or contributing to the 
adverse event; 
§ 
And the adverse event cannot be attributed solely to concurrent/underlying illness, 
other drugs, or procedures. 
o Event is probably not related to AZLI: 
§ 
A clinically plausible temporal sequence is inconsistent with the onset of the 
adverse event and AZLI administration; and/or 
§ 
A causal relationship is considered biologically implausible 
 


  E2.2 MedWatch 3500 Completion Methods 
• 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section B5) of the 
MedWatch 3500 form:  
o Identification of the primary event term 
o Protocol description (and number, if assigned) 
o Description of event, severity, treatment, and outcome if known 
o Supportive laboratory results and diagnostics 
o Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
o If a death occurred, autopsy results if available 
 
 E2.3 MedWatch 3500 Follow-up Information Methods 
• 
Additional information may be added to a previously submitted report by any of the following 
methods: 
o Add to the original MedWatch 3500 report and submit it as follow-up 
o Add documents and submit follow-up with the original MedWatch 3500 form 
o Summarize new information and fax it with a cover letter including subject identifiers (i.e. 
D.O.B., initial, subject number), protocol description and number, if assigned, brief adverse 
event description, and notation that additional or follow-up information is being 
submitted. (Patient identifiers are important so that new information is added to the 
correct initial report.) 
§ 
Occasionally, Gilead may contact the investigator for additional information, 
clarification, or current status of the subject for whom an adverse event was 
reported. 
 
E2.4 REPORTING OF ADVERSE EVENTS 
 
 E2.4.1 General Reporting of Serious Adverse Events Associated with AZLI 
• 
The Primary Investigator will report all SAEs to the IRB of the respective institutions involved. 
• 
All SAEs that are serious and reasonably or probably related to AZLI (this applies to both expected 
and unexpected events) along with all deaths should be recorded on a MedWatch 3500 Form faxed 
to: 
o Gilead Contact Information:  
  
E2.4.2 ADDITIONAL REPORTING REQUIREMENTS FOR IND HOLDERS FOR INVESTIGATOR SPONSORED IND 
STUDIES   N/A for our study. 
 
 E3. Risks/Benefits of Participation 
• 
There should be minimal risk to the subjects associated with participation in this study. Some of the 
subject may experience adverse effects of the study drug or placebo such as bronchospasm and/or 
hemoptysis.  
• 
Subjects will be carefully monitored by the medical team (Attending physician, pulmonary fellow, 
nursing staff, respiratory therapy staff), and the study coordinator for adverse events. If an adverse 
event occurs, the medical team and/or study coordinator will recognize it and the subject will be 
treated accordingly. If there is a temporary relationship between the study drug administration and 
the adverse event is deemed severe/serious by the PI, RSG, Gilead, the FDA, or the IRB, the subject 


will be treated as a drop out/treatment failure. The adverse event will be reported to the RSG, 
Gilead, and the IRB or the participating hospital. If deemed appropriate by any of the 
aforementioned groups, governmental agencies will also be notified of any adverse event. The 
reports will be made through telephone calls as well as written reports.  
• 
The data collected from subjects will be stored securely in either a locked storage container (paper 
data) or password restricted electronic medium (electronically collected/entered and analyzed 
data). All study personnel associated with this proposal will be reminded prior to the start and at 
regular intervals as to the necessity for keeping data confidential. Subjects will be identified by 
code and a code breaker sheet which associates the code to a name will be kept in a separate, 
locked storage container. 
• 
The benefits of participation in the proposal for the subjects are both direct and indirect. The direct 
benefits the subjects could potentially experience are an avoidance of intravenous antibiotic 
therapy due to Pseudomonas aeruginosa infection, if needed – a shorter duration of hospital stay 
due to lower bacterial burden of Pseudomonas. The indirect benefits the subjects could potentially 
experience include: less disruption in the family dynamic, decrease in hospital needs allowing 
parents to continue work, and collection of this data may provide for furthering of more studies 
using aztreonam and/or other inhaled antibiotics to eradicate colonization or decrease bacterial 
burden of lower respiratory tract bacterial infections.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


APPENDIX 
 
1) Study Checklist: 
 
Enrollment (Visit 0) 
1.  Consent 
o  
2.  Assent 
o  
3. HIPAA 
o 
4.  Demographic Form 
o  
5.  Eligibility Check list 
o 
6. Data Collection Form 
o 
7a.  + PsA trach cx in last 
month? 
o Yes      o No          
     7b.  If YES in 7a, then go to Visit 1  
o  
     7c.  If NO in 7a, then obtain tracheal aspirate culture  
            using sterile technique (see guidelines) and send  
            sample for bacterial culture 
o (check if sent culture during today’s visit) 
8.  Time Sheet 
o 
9. Chart review done completed by RW 
o Yes      o No          
 
 
Visit 1 
1.  Data Collection Form 
o  
2.  Obtain tracheostomy aspirate culture using sterile technique  
     (see guidelines) and send sample for bacterial culture 
o 
3.  AZLI Test Trial 
o 
4. Teach guardian how to deliver AZLI 
o 
5. Study drug (2 month supply*) given to participant. 
    * 2 month supply as will start on an ON month starting  
       tomorrow (day after Visit 1) 
o 
6.  Time Sheet 
o  
 
 
Visit 2 
1.  Data Collection Form 
o  
2.  Adverse Events Form 
o  
3.  Obtain tracheal aspirate culture using sterile technique  
     (see guidelines) and send sample for bacterial culture 
o 
4. Document results of Visit 1 culture on the Culture Results Form 
o 
5a. Obtain empty vials of the study drug from the participant. 
o 
5b. Document how many vials were returned and were used. 
___________  (max should be 168) 
6. Study drug (1 month supply*) given to participant. 
    * this quarter, will be on study drug once 
o 
7.  Time Sheet 
o  
 


Visit 3 
1.  Data Collection Form 
o  
2.  Adverse Events Form 
o  
3.  Obtain tracheal aspirate culture using sterile technique (see  
     guidelines) and send sample for bacterial culture 
o 
4. Document results of Visit 2 culture on the Culture Results Form 
o 
5a. Obtain empty vials of the study drug from the participant. 
o 
5b. Document how many vials were returned and were used. 
_____________(max should be 84) 
6. Study drug (2 month supply*) given to participant. 
    * this quarter, will be on study drug  twice 
o 
7.  Time Sheet 
o  
 
 
Visit 4 
1.  Data Collection Form 
o  
2.  Adverse Events Form 
o  
3.  Obtain tracheal aspirate culture using sterile technique (see  
     guidelines) and send sample for bacterial culture 
o 
4. Document results of Visit 2 culture on the Culture Results Form 
o 
5a. Obtain empty vials of the study drug from the participant. 
o 
5b. Document how many vials were returned and were used. 
___________  (max should be 168) 
6. Study drug (1 month supply*) given to participant. 
    * this quarter, will be on study drug once 
o 
7.  Time Sheet 
o  
 
 
Visit 5 
1.  Data Collection Form 
o  
2.  Adverse Events Form 
o  
3.  Obtain tracheal aspirate culture using sterile technique (see  
     guidelines) and send sample for bacterial culture 
o 
4. Document results of Visit 2 culture on the Culture Results Form 
o 
5a. Obtain empty vials of the study drug from the participant. 
o 
5b. Document how many vials were returned and were used. 
_____________(max should be 84) 
6. Termination (Study Exit) Form* 
o 
7.  Time Sheet 
o  
* termination form to be filled out at the last study visit to verify the participant has completed the study 
and on what date. Or, it is to be used if the parent/guardian or participant if 18 years or older has 
withdrawn consent and why. 
 
Follow-up 
1.  3 month telephone follow-up Form 
o  
2.  6 month telephone follow-up Form 
o  
 
 


2) Time Sheet Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


3) Eligibility Checklist Form:  
 
Informed Consent and Subject Assent Criteria 
1) Has a parent/legal guardian appropriately signed and dated the informed 
consent? 
oYes          o No 
 
2) If YES, record the date that the form was signed. 
_ _  / _ _  / _ _ _ _ 
Mo   Day      Year 
3) If the participant is 7-17 years of age, has the participant appropriately 
given verbal consent? 
oYes          o No 
4) If YES, record the date that verbal consent was given. 
_ _  / _ _  / _ _ _ _ 
Mo   Day      Year 
Medical History Criteria 
5) Is the participant 7-21 years old? 
oYes          o No 
6) Has the participant had a positive tracheostomy tube aspirate culture 
positive for Pseudomonas in the past? 
oYes          o No 
7) Has the participant been admitted to the hospital for respiratory related 
problems requiring antibiotics while having a tracheostomy tube? 
oYes          o No 
8) Has the participant smoked any type of tobacco products or other 
products in the last 12 months? 
oYes          o No 
9) Has the participant had inhaled antibiotics in the last 6 months? 
oYes          o No 
10) Does the patient have any of the following conditions: 
 
oCF (cystic fibrosis)         o PCD (primary ciliary dyskinesia)            o Tuberculosis                   
o Bronchiectasis              o previous culture positive for Burkholderia cepacia 
 
11) Does the participant have a significant medical illness other than asthma (mark all that apply)? 
 
o Congenital heart disease     o Neuromuscular disease     o Cerebral palsy    o Asthma   
o Other: _____________________________           o N/A 
 
12) Does the participant have a history of pulmonary edema or hemoptysis 
in the last 48 hours? 
oYes          o No 
13) Does the participant have a history of an adverse reaction to inhaled 
aztreonam? 
oYes          o No 
14) Is the participant in respiratory failure? 
oYes          o No 
Other Criteria 
16) Date of Birth  _ _  / _ _  / _ _ _ _ 
                               Mo    Day      Year 
16) Gender:              o Male              o Female 
17a) Mother’s ethnicity: 
o Caucasian        o Hispanic        o African Amer.        o Native Amer.        o Asian Amer.        o Other 
17b) Father’s ethnicity: 
o Caucasian        o Hispanic        o African Amer.        o Native Amer.        o Asian Amer.        o Other 
17c) Participant’s ethnicity: 
o Caucasian        o Hispanic        o African Amer.        o Native Amer.        o Asian Amer.        o Other 
18a) Mother’s Education:  ________________ years completed 


18b) Father’s Education:  ________________ years completed 
19) Does anyone living with the participant smoke?  (mark all that apply) 
o Mother        o Father        o Other: _______________ 
20a) Is there any other reason why this participant should not be in this study?    oYes          o No 
19b)If YES, please describe: _______________________________________________________ 
 
 
21) Is the participant eligible? If any of the shaded boxes are selected, mark No.       oYes          o No 
21a) If NO, participant is ineligible for the study. STOP HERE, thank participant and family for 
helping with the study, and complete Termination Form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
4) Demographic Data Form 
 
Participant’s Information 
 
1) Name:    _______________________       _______________________       _______________________    
                                       First                                                 Middle                                                Last 
 
2) Primary Care Physician / Clinic:  ________________________________________________________ 
3) Phone #:  
 
• 
Primary:       (________)  __________ - _____________________  (Home/Mobile/Work) 
• 
Secondary:  (________)  __________ - _____________________  (Home/Mobile/Work) 
 
4) Address:   
• 
______________________________________________________________________________ 
                                                                    Street Address 
 
• 
__________________________________________    _______    __________________________ 
                                       City                                                      State                           Zip 
 
• 
______________________________________________________________________________ 
                                 Mailing Address (if different from above Street Address) 
 
• 
__________________________________________    _______    __________________________ 
                                       City                                                      State                           Zip 
 
Medical History  
5) Does the participant have a tracheostomy tube? 
oYes          o No 
6) If YES, when was the tracheostomy tube placed? 
_ _  / _ _  / _ _ _ _ 
Mo   Day      Year 
7) Does the participant require a ventilator? 
• 
If YES, does he/she need it 24 hours a day? 
oYes          o No 
oYes          o No 
8) Does the participant see a pulmonologist? 
oYes          o No 
9) Does the participant take any regular medications for asthma or 
breathing problems? 
• 
If YES, what are the medications: 
o Albuterol       o Xoponex     o QVAR           o Flovent      
o Pulmicort      o Advair          o Symbicort   o Dulera                
o Prednisone   o Singulair 
oYes          o No 
10) How many times in the last year has the participant received antibiotics for a respiratory infection? 
 
o none     o 1     o 2     o 3     o 4 or more 
 
11) How many times in the last year has the participant been hospitalized for a respiratory infection? 
 
o none     o 1     o 2     o 3     o 4 or more 


12) Has the patient been hospitalized in the past for respiratory problems 
while having a tracheostomy tube: 
 
oYes          o No 
13) Regarding the tracheostomy tube that the participant has: 
• 
What brand is it?           o Bivona     o Shiley 
• 
Cuffed?                            o Yes           o No 
14) How often do you do trach changes 
• 
When well:____________________________ 
• 
When sick:_____________________________ 
15) Does the patient use the following (check all that apply): 
• 
Cool mist:                 oYes          o No 
• 
HME:                         oYes          o No 
• 
Speaking valve         oYes          o No 
- If YES, what type____________________ 
• 
In-line ventilator humidification     oYes          o No 
16) Does the participant have a history of an adverse reaction to inhaled 
aztreonam? 
oYes          o No 
17) Does the participant have any allergies? 
oYes          o No 
18) What medications does the participant take? (please list all of them) 
 
 
 
 
 
 
 
 
 
 
 
19) Does the participant have any other medical problems? (If YES, please list all of them) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Social History 
20) Are there any pets in the home (mark all that apply): 
o none     o cat     o dog     o bird     o other: _______________ 


 
21) Do you know of any mold in the participant’s home? 
oYes          o No 
22) Are there any smokers in the home? 
oYes          o No 
Family History 
23) Please list the medical problems of the family members of the participant in this study:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
5) Data Collection Form: 
 
 
Physical Exam: 
1.  Participant’s Height:__ __ __.__ cm   
              2.  Participant’s Weight:__ __ __.__ kg  
3.  O2 saturation:  __ __% in RA  / __ __lpm  O2  
4.  Respiratory rate: __ __ __ bpm 
5.  Heart rate:  __ __ __ bpm 
 
 
 
6.  Temperature:  __ __.__ oC 
7a. Tracheostomy tube type:        o Shiley               o Bivona            o Other__________________________    
7b. Tracheostomy tube size: _______ 
7c. Tracheostomy tube cuffed?    o Yes      o No          
         If YES in 7c, how much is it inflated?______________________________________________________ 
         If YES in 7c, how many hours per day is cuff inflated?________________________________________ 
7d. Tracheostomy tube cuff type :       o TTS          o Air cuff         o Fome cuff 
7e. Tracheostomoy tube cannula:        o single cannula                  o dual (inner and outer cannula)  
                                                                    o fenestrated 
8a. Ventilator dependent:              o Yes          o No 
8b. If YES on 8a, when does patient need ventilator:   o at all times     o with sleep     o Other__________ 
8c. If YES on 8a, how many hours per day is participant on the ventilator?___________________________ 
9a. Chest auscultation is clear:           o Yes          o No 
       9b.  If NO, circle all findings that apply: 
1. Expiratory wheeze 
 
2. Inspiratory wheeze 
                  3. Prolonged expiration 
4. Decreased breath sounds 
 
5. Retractions 
                  6. Tachypnea  
7. Crackles 
 
8. Wet cough 
 
9. Dry cough 
Study Medication: (skip if filling out on Visit 0 = Enrollment) 
10a. Did the participant bring the empty AZLI vials they have used since the last study visit?  o Yes      o No 
        10b. If YES, how many vials did they bring:_____________ (should be 84 per cycle = 28 days TID) 
11a. Is the participant currently receiving the study medication (ON cycle)?   o Yes         o No 
11b. Which week of current cycle is patient on (ie. week 1, 2, 3, or 4):      o 1      o 2      o 3      o 4 
Systemic Antibiotics and Hospitalization: 
12a. Has the participant received antibiotics in the last 3 months?     o Yes         o No 
12b. If YES in 12a, was it for a respiratory infection?     o Yes         o No 
         **Respiratory infection defined as meeting 3 of the 6 following criteria: fever, hypoxemia (SpO2 <  
              92%), cough, increased tracheal secretions, change in color of secretions from clear and/or white,  
              and radiographic evidence of pneumonia. 
12c. If YES in 12a, what type of antibiotic did the participant receive? _______________________________ 
12d. If YES  in 12a, was the drug IV (intravenous) or oral/feeding tube?     o IV     o Oral or via feeding tube 
13a. Has the patient been hospitalized in the last 3 months for respiratory problems?     o Yes         o No 
13b. If YES in 13a, please describe length of stay, treatment, oxygen need, respiratory support:__________ 
_______________________________________________________________________________________ 
14a. Is the participant currently receiving medications other than the study drug?      o Yes         o No 
14b. If YES, please list (may continue on the back of this form) 
Drug 
Start Date 
Dose 
Frequency 
End Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
6) Culture Results Form 
 
*** PLEASE PRINT CULTURE RESULTS ONCE THEY ARE FINAL, AND SAVE IN STUDY FILE*** 
 
Enrollment/Visit 1 
culture 
Culture collection date: 
 
Culture results: 
 
 
CFUs (if applicable): 
 
 
MIC: 
 
 
Sensitivities:  
 
 
 
Visit 2 Culture 
Culture collection date: 
 
Culture results: 
 
 
CFUs (if applicable): 
 
 
MIC: 
 
 
Sensitivities:  


Visit 3 Culture 
Culture collection date: 
 
Culture results: 
 
 
CFUs (if applicable): 
 
 
MIC: 
 
 
Sensitivities: 
Visit 4 Culture 
Culture collection date: 
 
Culture results: 
 
 
CFUs (if applicable): 
 
 
MIC: 
 
 
Sensitivities: 
Visit 5 Culture 
Culture collection date: 
 
Culture results: 
 
 
CFUs (if applicable): 
 
 
MIC: 
 
 
Sensitivities: 


Follow-up 
Culture collection date: 
 
Culture results: 
 
 
CFUs (if applicable): 
 
 
MIC: 
 
 
Sensitivities: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


7a) Adverse Events Participant Form 
 
  
How have you/your child felt sick since your last visit? 
oYes          o No 
Have you/your child had any health problems since you were last here? 
oYes          o No 
Have you/your child had any unusual or unexpected worsening of your underlying 
medical condition? 
oYes          o No 
Have you/ your child experienced coughing while taking the inhaled medication? 
oYes          o No 
Have you or your child experienced or been told by your physician one of the 
following: 
 
• 
Cough 
oYes          o No 
• 
Chest congestion 
oYes          o No 
• 
Throat pain 
oYes          o No 
• 
Throat irritation 
oYes          o No 
• 
Hoarse voice 
oYes          o No 
• 
Nasal congestion 
oYes          o No 
• 
Shortness of breath 
oYes          o No 
• 
Coughing up blood 
oYes          o No 
• 
Runny nose 
oYes          o No 
• 
Wheezing 
oYes          o No 
• 
Chest discomfort 
oYes          o No 
• 
Crackles on lung exam that your physician has told you 
oYes          o No 
• 
Pulmonary function testing decreased (if you had an lung function testing) 
oYes          o No 
• 
Non-cardiac chest pain 
oYes          o No 
• 
Sinus congestion 
oYes          o No 
• 
Sinus headache 
oYes          o No 
• 
Worsening shortness of breath 
oYes          o No 
• 
Shortness of breath on exertion 
oYes          o No 
Other (please write response): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
7b) Adverse Event Reporting Form 
 
 
 
 
 
 
 


 
7c) FDA MedWatch 3500 Form: 
Go to www. Patientsafetyasap.org/pdf/FDA-Voluntary%20Reporting.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
8) Termination of Participation (Study Exit) Form: 
 
1) Has the participant completed the study? 
• 
If YES, skip to signatures portion of this form 
oYes          o No 
2) Participant qualifies for the study based on eligibility criteria (See Eligibility 
Form). 
• 
If NO, skip to signatures portion of this form. 
oYes          o No 
3) Parent/guardian or participant if 18 years old or older, has withdrawn consent? 
• 
If YES, why (choose one)? 
• 
Parent/guardian no longer wishes to participate 
• 
Participant no longer wises to participate 
• 
Other________________________________________ 
_____________________________________________ 
oYes          o No 
 
4) Did the participant experience an adverse reaction? 
• 
If YES, what (choose one): 
o cough     o chest congestion     o throat pain     o throat irritation 
o hoarse voice     o nasal congestion     o shortness of breath 
o coughing up blood     o runny nose     o wheezing      
o chest discomfort     o crackles on lung exam     o sinus congestion 
o decrease on pulmonary function testing     o non-cardiac chest pain 
o sinus headache     o worsening shortness of breath 
o shortness of breath on exertion 
o respiratory failure: defined as: 1) pCO2 >60 mmHg; 2) oxygen 
requirement > 5 L/min; and 3) Invasive or non-invasive ventilation) 
and/or worsening of their clinical status (such as refractory coughing) 
during the trial. (automatic treatment failure) 
o other (please write response):________________________________ 
___________________________________________________________ 
 
oYes          o No 
 
Signatures 
Please complete the following section regardless of the reason for study termination. 
 
I verify that all information collected for this child is correct to the best of my knowledge and has been 
done so in accordance with the Manual of Procedures. 
 
 
____________________________________________                        ___ ___ / ___ ___ / ___ ___ ___ ___ 
                 Coordinator/Study Staff Signature                                              Mo             Day                  Year 
 
 
____________________________________________                        ___ ___ / ___ ___ / ___ ___ ___ ___ 
                 Principal Investigator  Signature                                                  Mo             Day                  Year 
 
 
 


 
9a and b) 3 and 6 Month Follow-up Form 
 
At Follow Up (Telephone call to primary pulmonologist or ENT physician) 
 
1) Date of completion of study: 
_ _  / _ _  / _ _ _ _ 
Mo      Day       Year 
2) Did the subject continue on inhaled 
Aztreonam on a 28 days on / 28 days off 
cycle? 
 
oYes          o No 
3) Has the subject had any respiratory 
exacerbations requiring systemic (IV or 
oral) antibiotics?  
 
 
oYes          o No 
 
4) Has the subject had any respiratory 
exacerbations requiring hospitalization?  
 
oYes          o No 
 
5) Has the subject had a recent 
tracheostomy aspirate culture? 
 
 
oYes          o No 
 
       5a) If YES, please provide results   
              including culture results, CFUs, MIC   
              and sensitivities. 
Culture collection date: 
 
Culture results: 
 
 
CFUs (if applicable): 
 
 
 
MIC: 
 
 
 
Sensitivities:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
10) Trach Aspirate Protocol: 
 
 
Obtaining a Sterile Tracheal Aspirate for Culture 
 
Assemble needed equipment:  
• 
Wall suction or portable suction with adjustable suction regulator and manometer, vacuum 
bottle, connecting tubing. 
• 
Suction catheter kit of appropriate size (new and unused). This will include sterile gloves. The 
size of the suction catheter should be about half the size of the inner diameter of the 
tracheostomy tube; or tracheostomy size x 2 = size Fr catheter to use. Too large a catheter will 
occlude the tracheostomy and transmit the full force of suction to the lungs. Too small a 
catheter may be ineffective. 
• 
Sterile specimen Trap 40 ml.  
• 
Normal saline, without preservatives. 
 
Clean and sanitize hands.  
Gown, glove and mask. 
Using the portable or wall suction: attach sterile specimen trap to the 6 foot suction tubing. 
Open sterile suction catheter kit and add some sterile saline to the sterile basin. 
Don sterile gloves.  
Measure the suction catheter based on tracheostomy tube length so you know how far to place the 
catheter in the tracheostomy tube. 
Hold catheter in dominate hand. Using other hand, attach catheter to the rubber tube of the sterile 
specimen trap.  
Ask nurse or parent to temporarily disconnect patient from circuit if they use a ventilator.  
Suction patient with correct technique to avoid tracheal trauma. 
Ask nurse or parent to re-connect patient to circuit if they use a ventilator. 
Use sterile saline (maximum of 5ml) to clear suction catheter and secretions into sterile specimen trap.  
Disconnect sterile specimen trap and properly seal (specimen trap comes with a sterile lid to seal 
specimen) and store specimen in specimen bag. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


11) Study Drug Break Form: 
 
1) Was the study drug discontinued or held? 
 
oYes          o No 
2) If yes, please specify the dates study drug was held:  
 
3) If yes in question 1, was it due to being hospitalized? 
 
oYes          o No 
4) If yes in question 1, was it due to being requiring antibiotics at home? 
 
oYes          o No 
 
5) If yes in question 1, but not due to hospitalization or need for antibiotics at home, please write down 
the reason: 
 
 
 
 
Signatures 
Please complete the following section regardless of the reason for study deviation. 
 
I verify that all information collected for this child is correct to the best of my knowledge and has been 
done so in accordance with the Manual of Procedures. 
 
 
____________________________________________                        ___ ___ / ___ ___ / ___ ___ ___ ___ 
                 Coordinator/Study Staff Signature                                              Mo             Day                 Year 
 
 
____________________________________________                        ___ ___ / ___ ___ / ___ ___ ___ ___ 
                 Principal Investigator  Signature                                                  Mo             Day                 Year 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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