Aztreonam Lysine for Pseudomonas Infection Eradication Study

Open-Label Phase 2 Trial to Evaluate the Safety and Efficacy of Aztreonam 75 mg Powder and Solvent for Nebuliser Solution/Aztreonam for Inhalation Solution (AZLI) in Pediatric Patients With Cystic Fibrosis (CF) and New Onset Lower Respiratory Tract Culture Positive for Pseudomonas Aeruginosa (PA)

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01375049

Acronym

ALPINE

Enrollment

105

Registered

2011-06-17

Start date

2011-08-31

Completion date

2013-05-31

Last updated

2014-07-17

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cystic Fibrosis

Keywords

Cystic fibrosis, CF, PA, Pseudomonas aeruginosa, AZLI, aztreonam

Brief summary

This is an open-label, multi-center study in pediatric patients age 3 months to less than 18 years with cystic fibrosis (CF) and newly detected Pseudomonas aeruginosa (PA) pulmonary colonization/infection. All eligible participants will be treated with a 28-day course of Aztreonam for Inhalation Solution (AZLI) 75 mg 3 times daily. After completion of study drug, subjects will be followed up through Day 196 for safety and recurrence of PA. The primary objective is to evaluate the proportion of participants with PA-negative cultures at all time points during a 6-month monitoring period (through Day 196) after cessation of AZLI treatment. Microbiological cultures will be obtained at Baseline, Day 28 (end of AZLI treatment), Day 56 (1 month after completing AZLI treatment), Day 112 (3 months after completing AZLI treatment), and Day 196 (6 months after completing AZLI treatment).

Interventions

DRUGAztreonam for Inhalation Solution (AZLI)

AZLI 75 mg administered 3 times daily via the investigational eFlow® nebulizer

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

3 Months to 17 Years

Healthy volunteers

Inclusion criteria

* Males or females age 3 months to less than 18 years * Diagnosis of CF as determined by the 1997 CF Consensus Conference criteria: * Documented sweat chloride ≥ 60 mEq/L by quantitative pilocarpine iontophoresis test OR * Abnormal nasal transepithelial potential difference test OR * Two well-characterized, disease-causing genetic mutations in the CF transmembrane conductance regulator (CFTR) gene AND * One or more clinical features consistent with CF * Documented new onset of positive lower respiratory tract culture (e.g., throat swab, sputum, or BAL) for PA within 30 days of study entry (prior to screening visit) defined as either first lifetime documented PA-positive culture OR PA recovered after at least a 2 year history of PA-negative respiratory cultures (at least 2 cultures per year) * Forced expiratory volume in 1 second (FEV1) ≥ 80% predicted at screening visit (subjects ≥ 6 years of age) * Clinically stable with no evidence of significant respiratory symptoms or, if obtained for clinical evaluation, no chest radiograph findings at screening that would have required administration of IV antipseudomonal antibiotics, oxygen supplementation, or hospitalization. * All sexually active females who were of childbearing potential must agree to use a highly effective method of contraception during heterosexual intercourse throughout the study. Females utilizing hormonal contraceptives as a birth control method must have used the same method for at least 3 months prior to study drug dosing. * Males must agree to use barrier contraception (condom with spermicide) during heterosexual intercourse from screening through to study completion and for 90 days from the last dose of study investigational medicinal product * Participants and/or parent/guardian must be able to give written informed consent prior to any study related procedure

Exclusion criteria

* Use of IV or inhaled antipseudomonal antibiotics within 2 years of study entry (screening visit) * Use of oral antipseudomonal antibiotics within 30 days of study entry (screening visit) * History of sputum or throat swab culture yielding Burkholderia spp. within 2 years prior to screening visit * History of local or systemic hypersensitivity to monobactam antibiotics * History of intolerance to inhaled short acting beta 2 agonists * History of lung transplantation * History of AZLI (or Cayston®) administration * Administration of any investigational drug or device within 28 days prior to screening visit or within 6 half-lives of the investigational drug (whichever is longer) * Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone per day or 20 mg prednisone every other day * Current requirement for daily continuous oxygen supplementation or requirement of more than 2 L/minute at night * Hospitalization for pulmonary-related illness within 28 days prior to screening visit * Changes in or initiation of chronic azithromycin treatment within 28 days prior to screening visit * Changes in antimicrobial, bronchodilator (BD), corticosteroid, dornase alfa, or hypertonic saline medications within 7 days prior to screening visit; for participants on a stable regimen of hypertonic saline (28 days on/28 days off), beginning or ending a cycle of hypertonic saline is allowed * Changes in physiotherapy technique or schedule within 7 days prior to screening visit * Abnormal renal or hepatic function results at most recent test within the previous 12 months, defined as: * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 5 times upper limit of normal (ULN), or * Serum creatinine \> 2 times ULN for age * Pregnant or lactating females; a negative urine pregnancy test is required for all females of childbearing potential (unless surgically sterile), and confirmatory serum pregnancy test in the event of an initial positive urine test result * Any serious or active medical or psychiatric illness (including drug or alcohol abuse), which in the opinion of the investigator, would interfere with treatment, assessment, or compliance with the protocol * Presence of a condition or abnormality that would compromise the patient's safety or the quality of study data, in the opinion of the investigator

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With PA-negative Cultures at All Time Points After Cessation of Active Treatment (Evaluable Analysis Set)	Day 28 to Day 196	The percentage of participants with PA-negative cultures at all time points after cessation of active treatment at Day 28 (assessed at Days 56, 112, and 196) was summarized for the Evaluable Analysis Set.
Percentage of Participants With PA-negative Cultures at All Time Points After Cessation of Active Treatment (Sensitivity Analysis Set)	Day 28 to Day 196	The percentage of participants with PA-negative cultures at all time points after cessation of active treatment at Day 28 (assessed at Days 56, 112, and 196) was summarized for the Sensitivity Analysis Set.

Secondary

Measure	Time frame	Description
Percentage of Participants With PA-negative Cultures	Days 28, 56, 112, and 196	The percentage of participants with a PA-negative culture was summarized at each visit.
Use of Additional (Non-study) Antipseudomonal Antibiotics	Baseline to Day 196	The percentage of participants who used additional (non-study) antipseudomonal antibiotics (an indication of PA exacerbation) while on treatment and posttreatment was summarized.
Change From Baseline in Weight	Baseline to Days 28, 56, 112, and 196	—
Change From Baseline in FEV1% Predicted	Baseline to Days 28, 56, 112, and 196	Spirometry assessments were performed only in participants ≥ 6 years of age. Forced expiratory volume in 1 second (FEV1) % predicted was defined as FEV1 of the participant divided by the average FEV1 in the population for any person of similar age, sex and body composition.
Change From Baseline in Body Mass Index (BMI)	Baseline to Days 28, 56, 112, and 196	—
Pharmacokinetics (PK) Peak and Trough Plasma Concentrations of Aztreonam	Day 1 (1 hour postdose) and Day 28 (immediately prior to dosing)	The plasma concentration of aztreonam for participants \< 6 years of age was obtained 1 hour after the first dose of AZLI on Day 1 and immediately prior to the last dose of AZLI on Day 28.
Change From Baseline in Height	Baseline to Days 28, 56, 112, and 196	—
Change From Baseline in CFQ-R RSS Score	Baseline to Days 28, 56, 112, and 196	Respiratory symptoms (eg, coughing, congestion, wheezing) were assessed with the Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) only in participants ≥ 6 years of age. The range of scores (units) is 0 to 100 with higher scores indicating fewer symptoms.

Countries

Austria, Belgium, France, Germany, Italy, Netherlands, Poland, Spain, United States

Participant flow

Recruitment details

Participants were enrolled at a total of 46 study sites in the United States and Europe. The first participant was screened on 04 October 2011. The last participant observation occurred on 29 May 2013.

Pre-assignment details

109 participants were screened; 105 participants were enrolled and treated, and comprise the Safety Analysis Set and the Full Analysis Set.

Participants by arm

Arm	Count
AZLI Participants received one 28-day course of AZLI, then were followed for a 24-week period (through Day 196). AZLI 75 mg was administered 3 times daily via the investigational eFlow® nebulizer.	105
Total	105

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	2
Overall Study	Lost to Follow-up	1
Overall Study	Protocol-Specified Withdrawal Criteria	45
Overall Study	Withdrawal by Subject	2

Baseline characteristics

Characteristic	AZLI
Age, Continuous	6.26 years STANDARD_DEVIATION 4.743
Age, Customized ≥ 2 years to < 6 years	25 participants
Age, Customized 3 months to < 2 years	24 participants
Age, Customized ≥ 6 years to < 18 years	56 participants
BMI	17.1 kg/m^2 STANDARD_DEVIATION 2.57
Height	113.9 cm STANDARD_DEVIATION 33.02
Presence of Pseudomonas aeruginosa (PA) Absent at baseline	57 participants
Presence of Pseudomonas aeruginosa (PA) Present at baseline	45 participants
Race/Ethnicity, Customized Asian	1 participants
Race/Ethnicity, Customized Black or African Heritage	1 participants
Race/Ethnicity, Customized Hispanic	5 participants
Race/Ethnicity, Customized Not Hispanic	93 participants
Race/Ethnicity, Customized Not Permitted to be Recorded	2 participants
Race/Ethnicity, Customized Other	2 participants
Race/Ethnicity, Customized White	99 participants
Region of Enrollment Austria	3 participants
Region of Enrollment Belgium	11 participants
Region of Enrollment France	12 participants
Region of Enrollment Germany	4 participants
Region of Enrollment Italy	5 participants
Region of Enrollment Netherlands	5 participants
Region of Enrollment Poland	3 participants
Region of Enrollment Spain	6 participants
Region of Enrollment United States	56 participants
Sex: Female, Male Female	47 Participants
Sex: Female, Male Male	58 Participants
Weight	24.8 kg STANDARD_DEVIATION 15.69

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	66 / 105
serious Total, serious adverse events	8 / 105

Outcome results

Primary

Percentage of Participants With PA-negative Cultures at All Time Points After Cessation of Active Treatment (Evaluable Analysis Set)

The percentage of participants with PA-negative cultures at all time points after cessation of active treatment at Day 28 (assessed at Days 56, 112, and 196) was summarized for the Evaluable Analysis Set.

Time frame: Day 28 to Day 196

Population: Evaluable Analysis Set

Arm	Measure	Value (NUMBER)
AZLI - Evaluable Analysis Set	Percentage of Participants With PA-negative Cultures at All Time Points After Cessation of Active Treatment (Evaluable Analysis Set)	58.2 percentage of participants

Primary

Percentage of Participants With PA-negative Cultures at All Time Points After Cessation of Active Treatment (Sensitivity Analysis Set)

Time frame: Day 28 to Day 196

Population: Sensitivity Analysis Set

Arm	Measure	Value (NUMBER)
AZLI - Evaluable Analysis Set	Percentage of Participants With PA-negative Cultures at All Time Points After Cessation of Active Treatment (Sensitivity Analysis Set)	46.9 percentage of participants

Secondary