Aztreonam for Inhalation Solution vs Tobramycin Inhalation Solution in Patients With Cystic Fibrosis & Pseudomonas Aeruginosa

Condition(s) targeted: Cystic Fibrosis

Intervention: Aztreonam for Inhalation Solution (AZLI) (Drug); Tobramycin Inhalation Solution (TIS) (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Gilead Sciences

Official(s) and/or principal investigator(s):
Mark Bresnik, MD, Study Director, Affiliation: Gilead Sciences

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.

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 design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted at Day 28

Mean Actual Change From Baseline in FEV1 Percent Predicted Across 3 Treatment Courses

Secondary outcome:

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

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

Time to Need for Intravenous (IV) Antipseudomonal Antibiotics for Respiratory Events

Time to First Respiratory Hospitalization

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.

Minimum age: 6 Years. Maximum age: N/A. Gender(s): Both.

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

Innsbruck A-6020, Austria

Salzburg A-5020, Austria

Antwerp 2650, Belgium

Brussels 1090, Belgium

Bruxelles 1070, Belgium

Ghent 9000, Belgium

Leuven 3000, Belgium

Copenhagen DK-2100, Denmark

Amiens 80054, France

Bordeaux 33076, France

Caen 14000, France

Creteil 94000, France

Lille Cedex 59037, France

Lisieux 14100, France

Montpellier 34295, France

Nice cedex 3 06202, France

Paris Cedex 75743, France

Pessac Cedex 33604, France

Rennes 35033, France

Berlin 13125, Germany

Berlin 123353, Germany

Bochum 44791, Germany

Essen 45122, Germany

Essen 45239, Germany

Giessen 35392, Germany

Hamburg 22763, Germany

Leipzig 04103, Germany

Magdeburg 39120, Germany

Mainz 55101, Germany

Munchen 80336, Germany

Dublin, Ireland

Dublin 4, Ireland

Dublin 9, Ireland

Dublin 24, Ireland

Galway, Ireland

Ancona 60123, Italy

Catania 95123, Italy

Milano 20122, Italy

Napoli 80131, Italy

Palermo 90134, Italy

Parma 43100, Italy

Rome 00161, Italy

Rome 00165, Italy

Verona 37126, Italy

Den Haag 2504 LN, Netherlands

Maastricht 6229, Netherlands

Lisboa 1649-035, Portugal

Porto 4200 319, Portugal

Madrid 28009, Spain

Madrid 28034, Spain

Madrid 28041, Spain

Madrid 28046, Spain

Malaga 29011, Spain

Zurich CH - 8032, Switzerland

Zurich CH - 8091, Switzerland

Belfast BT9 7AB, United Kingdom

Cambridge CB23 3RE, United Kingdom

Cardiff CF64-2XX, United Kingdom

Leeds LS9 7TF, United Kingdom

Liverpool L14 3PE, United Kingdom

London SW3 6NP, United Kingdom

Southampton SO16 6YD, United Kingdom

Anchorage, Alaska 99508, United States

Phoenix, Arizona 85006, United States

Tuscon, Arizona 85724, United States

Orange, California 92868, United States

Aurora, Colorado 80045, United States

Denver, Colorado 80206, United States

Wilmington, Delaware 19803, United States

Orlando, Florida 32801, United States

Tampa, Florida 33606, United States

Chicago, Illinois 60637, United States

Glenview, Illinois 60025, United States

Niles, Illinois 60714, United States

Boston, Massachusetts 02115, United States

Columbia, Missouri 65212, United States

Las Vegas, Nevada 89107, United States

Albany, New York 12208, United States

New Hyde Park, New York 11040, United States

Cincinnati, Ohio 45229, United States

Dayton, Ohio 45404, United States

Toledo, Ohio 43606, United States

Oklahoma City, Oklahoma 73112, United States

Hershey, Pennsylvania 17033, United States

Philadelphia, Pennsylvania 19102, United States

Philadelphia, Pennsylvania 19104, United States

Charleston, South Carolina 29425, United States

Houston, Texas 77030, United States

San Antonio, Texas 78212, United States

Salt Lake City, Utah 84132, United States

Richmond, Virginia 23298, United States

Sheffield, West Yorkshire S10 2TH, United Kingdom

Starting date: August 2008
Last updated: June 7, 2011