Clinical trial NCT00757237: Aztreonam for Inhalation Solution vs Tobramycin Inhalation Solution in Patients With Cystic Fibrosis & Pseudomonas Aeruginosa
Official title: An Open-Label, Randomized, Phase 3 Trial to Evaluate the Efficacy and Safety of Aztreonam for Inhalation Solution (AZLI) Versus Tobramycin Inhalation Solution (TIS) in an Intermittent Aerosolized Antibiotic Regimen in Subjects With Cystic Fibrosis Followed by an Open-Label, Single Arm Extension (European Union [EU] Only)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cystic Fibrosis
Keywords: aztreonam lysine
tobramycin inhalation solution
tobramycin nebuliser solution
cystic fibrosis
pseudomonas aeruginosa
lung infection
CFQ-R
inhaled antibiotic
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
Collaborators: name: Chiltern International Inc.
name: ClinPhone, Inc.
name: Covance
First posted: 2008-09-23
Enrollment: 274
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to assess the comparative safety and effectiveness of aztreonam for inhalation solution versus tobramycin inhalation solution in adult and pediatric patients with cystic fibrosis (CF) and pulmonary Pseudomonas aeruginosa (PA) infection.

Detailed description: Number of Subjects Planned: Approximately 240 randomized patients

Target Population: CF patients \>= 6 years of age with stable pulmonary disease, who at study entry had a recent positive sputum culture for PA and had been previously treated with aerosolized antibiotics without demonstration of drug intolerance.

The randomized phase of this study, used for hypotheses testing, enrolled participants from both the United States (US) and EU. An open-label, single-arm extension was available for participants in the EU who completed at least one course of AZLI or TIS during the randomized portion of the study. These participants were eligible to receive 3 additional cycles of AZLI in a 28-day, intermittent, repeating treatment regimen. Results of the extension phase will be available the first quarter (Q1) of 2012.

Randomized Phase Study Design (US and EU): This was an open-label, multicenter, randomized, parallel group study. The study design consisted of 2 treatment arms of 28-day, intermittent, repeating treatment regimens: aztreonam for inhalation solution (AZLI) or tobramycin inhalation solution (TIS). The total study period was 26 weeks. The study schedule included 9 visits - Screening, Baseline, Day 14, Day 28, followed by visits every 28 days through the end of the study.

Eligibility criteria: Inclusion Criteria:

* Males or females aged 6 years and older
* Subjects with CF as diagnosed by one of the following: documented sweat chloride \>= 60 mEq/L by quantitative pilocarpine iontophoresis test, or documented sweat sodium \>= 60 mmol/L, or 2 well characterized genetic mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, or abnormal nasal potential difference with accompanying symptoms characteristic of CF
* Documented PA in an expectorated sputum or throat swab culture within 3 months prior to Visit 1 or at Visit 1
* Subjects must be able to provide written informed consent/assent prior to any study related procedures; parent/guardian must be able to give written informed consent as necessary prior to any study related procedure
* Subjects must have received previous treatment with aerosolized antibiotics without demonstration of drug intolerance
* FEV1 \<= 75% predicted at Visit 1
* Ability to perform reproducible pulmonary function tests
* Chest radiograph at Visit 1 without significant acute findings (eg, infiltrates \[lobar or diffuse interstitial\], pleural effusion, pneumothorax); or chest radiograph or magnetic resonance image (MRI) obtained within the 180 days prior to Visit 1 without acute findings and no significant intercurrent illness; chronic, stable findings (eg, chronic scarring or atelectasis) are allowed

Exclusion Criteria:

* Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone a day or 20 mg prednisone every other day
* History of sputum or throat swab culture yielding B. cepacia in the previous 2 years
* Current requirement for daily continuous oxygen supplementation or requirement for more than 2 L/minute at night
* Administration of any investigational drug or device within 28 days of Visit 1 or within 6 half-lives of the investigational drug (whichever is longer)
* Known local or systemic hypersensitivity to monobactam antibiotics
* Known allergies/intolerance to tobramycin
* Inability to tolerate inhalation of a short acting beta agonist
* Changes in or initiation of chronic azithromycin treatment within 28 days prior to Visit 1
* Administration of antipseudomonal antibiotics by inhalation, intravenous or oral routes within the 14 days prior to Randomization/Visit 2
* Changes in antimicrobial, bronchodilator (BD), dornase alfa, or corticosteroid medications within 7 days prior to Visit 1
* Changes in physiotherapy technique or schedule within 7 days prior to Visit 1
* History of lung transplantation
* Abnormal renal or hepatic function or serum chemistry at Visit 1, defined as aspartate aminotransferase (AST), alanine aminotransferase (ALT) \> 5 times upper limit of normal range (ULN) or creatinine \> 2 times ULN
* Positive pregnancy test at Visit 1; all women of childbearing potential will be tested
* Female of childbearing potential who is lactating or is not (in the opinion of the investigator) practicing an acceptable method of birth control; female subjects who utilize hormonal contraceptives as one of their birth control methods must have used the same method for at least 3 months before study dosing
* Any serious or active medical or psychiatric illness, which in the opinion of the investigator, would interfere with patient treatment, assessment, or compliance with the protocol

Primary outcomes:
measure: Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted at Day 28
timeFrame: Baseline and end of treatment Course 1 (Day 28)
measure: Mean Actual Change From Baseline in FEV1 Percent Predicted Across 3 Treatment Courses
timeFrame: Baseline, and end of treatment Courses 1 (Week 4), 2 (Week 12), and 3 (Week 20)
Secondary outcomes:
measure: Relative Change From Baseline in FEV1 Percent Predicted at Day 28 in Subjects Who Received Inhaled Tobramycin for >= 84 Days in the 12 Months Prior to Randomization
timeFrame: Baseline and end of treatment Course 1 (Day 28)
measure: Mean Actual Change From Baseline in FEV1 Percent Predicted Across 3 Treatment Courses in Subjects Who Received Inhaled Tobramycin for >= 84 Days in the 12 Months Prior to Randomization
timeFrame: Baseline and end of treatment Courses 1 (Week 4), 2 (Week 12), and 3 (Week 20)
measure: Time to Need for Intravenous (IV) Antipseudomonal Antibiotics for Respiratory Events
timeFrame: Day 0 to Day 168 (end of study)
measure: Time to First Respiratory Hospitalization
timeFrame: Day 0 to Day 168 (end of study)
Other outcomes:
measure: Actual Change From Baseline in CF Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score at Day 28
timeFrame: Baseline and end of treatment Course 1 (Day 28)
measure: Mean Actual Change From Baseline in CFQ-R RSS Score Across 3 Treatment Courses
timeFrame: Baseline and end of treatment Courses 1 (Week 4), 2 (Week 12), and 3 (Week 20)
measure: Treatment Satisfaction Questionnaire for Medication (TSQM) - Global Satisfaction Results at Week 20
timeFrame: At Week 20
measure: Total Number of Respiratory Hospitalizations
timeFrame: Day 0 to Day 168 (end of study)
measure: Number of Respiratory Events Requiring IV and/or Inhaled Antipseudomonal Antibiotics (Other Than Randomized Treatment)
timeFrame: Day 0 through Day 168 (end of study)
measure: Time to Need for Inhaled and/or IV Antipseudomonal Antibiotics for Respiratory Event (Other Than Randomized Treatment)
timeFrame: Day 0 to Day 168 (end of study)
Locations:
city: Anchorage
country: United States
state: Alaska
city: Phoenix
country: United States
state: Arizona
city: Tuscon
country: United States
state: Arizona
city: Orange
country: United States
state: California
city: Aurora
country: United States
state: Colorado
city: Denver
country: United States
state: Colorado
city: Wilmington
country: United States
state: Delaware
city: Orlando
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: Chicago
country: United States
state: Illinois
city: Glenview
country: United States
state: Illinois
city: Niles
country: United States
state: Illinois
city: Boston
country: United States
state: Massachusetts
city: Columbia
country: United States
state: Missouri
city: Las Vegas
country: United States
state: Nevada
city: Albany
country: United States
state: New York
city: New Hyde Park
country: United States
state: New York
city: Cincinnati
country: United States
state: Ohio
city: Dayton
country: United States
state: Ohio
city: Toledo
country: United States
state: Ohio
city: Oklahoma City
country: United States
state: Oklahoma
city: Hershey
country: United States
state: Pennsylvania
city: Philadelphia
country: United States
state: Pennsylvania
city: Philadelphia
country: United States
state: Pennsylvania
city: Charleston
country: United States
state: South Carolina
city: Houston
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Salt Lake City
country: United States
state: Utah
city: Richmond
country: United States
state: Virginia
city: Innsbruck
country: Austria
city: Salzburg
country: Austria
city: Antwerp
country: Belgium
city: Brussels
country: Belgium
city: Bruxelles
country: Belgium
city: Ghent
country: Belgium
city: Leuven
country: Belgium
city: Copenhagen
country: Denmark
city: Amiens
country: France
city: Bordeaux
country: France
city: Caen
country: France
city: Creteil
country: France
city: Lille Cedex
country: France
city: Lisieux
country: France
city: Montpellier
country: France
city: Nice cedex 3
country: France
city: Paris Cedex
country: France
city: Pessac Cedex
country: France
city: Rennes
country: France
city: Berlin
country: Germany
city: Berlin
country: Germany
city: Bochum
country: Germany
city: Essen
country: Germany
city: Essen
country: Germany
city: Giessen
country: Germany
city: Hamburg
country: Germany
city: Leipzig
country: Germany
city: Magdeburg
country: Germany
city: Mainz
country: Germany
city: Munchen
country: Germany
city: Dublin
country: Ireland
city: Dublin
country: Ireland
city: Dublin
country: Ireland
city: Dublin
country: Ireland
city: Galway
country: Ireland
city: Ancona
country: Italy
city: Catania
country: Italy
city: Milano
country: Italy
city: Napoli
country: Italy
city: Palermo
country: Italy
city: Parma
country: Italy
city: Rome
country: Italy
city: Rome
country: Italy
city: Verona
country: Italy
city: Den Haag
country: Netherlands
city: Maastricht
country: Netherlands
city: Lisboa
country: Portugal
city: Porto
country: Portugal
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Malaga
country: Spain
city: Zurich
country: Switzerland
city: Zurich
country: Switzerland
city: Sheffield
country: United Kingdom
state: West Yorkshire
city: Belfast
country: United Kingdom
city: Cambridge
country: United Kingdom
city: Cardiff
country: United Kingdom
city: Leeds
country: United Kingdom
city: Liverpool
country: United Kingdom
city: London
country: United Kingdom
city: Southampton
country: United Kingdom
Study officials:
affiliation: Gilead Sciences
name: Mark Bresnik, MD
role: STUDY_DIRECTOR
References:
citation: Assael BM, Pressler T, Bilton D, Fayon M, Fischer R, Chiron R, LaRosa M, Knoop C, McElvaney N, Lewis SA, Bresnik M, Montgomery AB, Oermann CM; AZLI Active Comparator Study Group. Inhaled aztreonam lysine vs. inhaled tobramycin in cystic fibrosis: a comparative efficacy trial. J Cyst Fibros. 2013 Mar;12(2):130-40. doi: 10.1016/j.jcf.2012.07.006. Epub 2012 Sep 15.