Safety and Efficacy Study of Aztreonam for Inhalation Solution (AZLI) in Patients With Cystic Fibrosis and Chronic Burkholderia Species Infection

• ClinicalTrials.gov Identifier: NCT01059565
• Recruitment Status: Completed
• First Posted: February 1, 2010
• Results First Posted: March 11, 2014
• Last Update Posted: March 11, 2014
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Study Description

Brief Summary:

The purpose of this research study was to determine if an experimental drug called Aztreonam for Inhalation Solution (AZLI) was safe and effective to treat Burkholderia lung infections in patients with cystic fibrosis (CF).

Spirometry was used to assess pulmonary function, and the revised Cystic Fibrosis Questionnaire (CFQ-R) was used to assess quality of life. The CFQ-R is a validated, patient-reported outcome tool used to measure health-related quality of life for children and adults with CF.

The study consisted of a 24-week randomized phase, and a 24-week open-label phase. Primary and secondary efficacy analyses were conducted for the 24-week randomized phase only. Safety data were collected for both the randomized and open-label phases.

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis; Burkholderia Infections	Drug: AZLI; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 102 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 3b Randomized, Double-Blind, Placebo-Controlled Two-Part Trial to Assess the Safety and Efficacy of Continuous Aztreonam for Inhalation Solution (AZLI) in Subjects With Cystic Fibrosis (CF) and Chronic Burkholderia Species Infection
• Study Start Date: February 2010
• Actual Primary Completion Date: September 2011
• Actual Study Completion Date: January 2012

Arms and Interventions

Arm	Intervention/treatment
Experimental: AZLI; Participants were randomized to receive AZLI for up to 24 weeks and may have continued to receive AZLI during the open-label phase for up to an additional 24 weeks.	Drug: AZLI; Aztreonam for inhalation solution (AZLI; 75 mg aztreonam/52.5 mg lysine monohydrate) was administered three times a day, with at least 4 hours between doses, using the investigational nebulizer.
Placebo Comparator: Placebo; Participants were randomized to receive placebo to match AZLI for up to 24 weeks and may have switched to AZLI during the open-label phase for up to 24 weeks.	Drug: Placebo; Placebo to match AZLI (lactose and sodium chloride) was administered three times a day, with at least 4 hours between doses, using the investigational nebulizer.

Outcome Measures

Primary Outcome Measures :

1. AUCave of Relative Change in FEV1 % Predicted From Baseline to Week 24 [ Time Frame: Baseline to Week 24 ]
   The relative change (AUCave) in FEV1 % predicted from baseline to Week 24 was analyzed. FEV1 % predicted is defined as FEV1 % of the patient divided by the average FEV1 % in the population for any person of similar age, sex and body composition. AUCave is the calculated area under the curve corrected for baseline and adjusted by the number of days on study through Week 24.

Secondary Outcome Measures :

1. Total Number of Systemic and/or Inhaled Antibiotic Courses for Respiratory Events [ Time Frame: Baseline to Week 24 ]
   The total number of systemic and/or inhaled antibiotic courses for respiratory events from baseline to Week 24 was analyzed. A single antibiotic course may represent the use of multiple antibiotics.
2. AUCave of Change in CFQ-R RSS Scores From Baseline to Week 24 [ Time Frame: Baseline to Week 24 ]

   The change (AUCave) in CFQ-R RSS scores from baseline to Week 24 was analyzed.

   The range of scores (units) within the RSS domain is 0 to 100 with higher scores indicating fewer symptoms.

3. AUCave of Relative Change From Baseline to Week 24 in FEV1 [ Time Frame: Baseline to Week 24 ]
   The relative change (AUCave) from baseline to Week 24 in mean (SE) FEV1 was analyzed. FEV1 is defined as the maximal volume of air that can be exhaled in 1 second.
4. AUCave of Relative Change From Baseline to Week 24 in FVC [ Time Frame: Baseline to Week 24 ]
   The relative change (AUCave) from baseline to Week 24 in mean (SE) FVC was analyzed. FVC is defined as the volume of air that can forcibly be blown out after taking a full breath.
5. AUCave of Relative Change From Baseline to Week 24 in FEF25-75 [ Time Frame: Baseline to Week 24 ]
   The relative change (AUCave) from baseline to Week 24 in mean (SE) FEF25-75 was analyzed. FEF25-75 is defined as the forced expiratory flow from 25% to 75% of the FVC.
6. AUCave of the Change From Baseline to Week 24 in Physical Functioning Score as Assessed by the CFQ-R [ Time Frame: Baseline to Week 24 ]

   The change (AUCave) from baseline to Week 24 in the physical functioning score as assessed by the CFQ-R was analyzed.

   The range of scores (units) in the CFQ-R physical functioning domain is 0 to 100 with higher scores indicating better QOL.

7. AUCave of the Change From Baseline to Week 24 in Weight Score as Assessed by the CFQ-R [ Time Frame: Baseline to Week 24 ]

   The change (AUCave) from baseline to Week 24 in the weight score as assessed by the CFQ-R was analyzed.

   The range of scores (units) in the CFQ-R weight domain is 0 to 100 with higher scores indicating better QOL.

8. AUCave of the Change From Baseline to Week 24 in Treatment Burden Score as Assessed by the CFQ-R [ Time Frame: Baseline to Week 24 ]

   The change (AUCave) from baseline to Week 24 in the treatment burden score as assessed by the CFQ-R was analyzed.

   The range of scores (units) in the CFQ-R treatment burden domain is 0 to 100 with higher scores indicating better QOL.

9. Change in BMI From Baseline to Week 24 [ Time Frame: Baseline to Week 24 ]
   The change in BMI from baseline to Week 24 was analyzed.
10. Change in Burkholderia Spp. CFU in Sputum From Baseline to Week 24 [ Time Frame: Baseline to Week 24 ]
    The change in Burkholderia spp. CFU in sputum from baseline to Week 24 was analyzed.
11. Percentage of Days Participants Used Antibiotics [ Time Frame: Baseline to Week 24 ]
    The percentage of days participants used antibiotics from baseline to Week 24 was analyzed. Antibiotics ongoing at baseline or started on or after first dose date were included in the analysis. A single antibiotic course could represent the use of multiple antibiotics. Days of antibiotic use included unique days.
12. Percent of Days Hospitalized [ Time Frame: Baseline to Week 24 ]
    The percentage of days hospitalized from baseline to Week 24 was analyzed.
13. Percentage of Missed School or Work Days [ Time Frame: Baseline to Week 24 ]
    The percentage of days participants missed school or work from baseline to Week 24 was analyzed.

Eligibility Criteria

• Ages Eligible for Study: 6 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male or female ≥ 6 years of age

2. Subjects with CF as diagnosed by one of the following:

   • Documented sweat chloride ≥ 60 milliequivalent (mEq)/L by quantitative pilocarpine iontophoresis test
   • Documented sweat sodium ≥ 60 mmol/L
   • Two well-characterized genetic mutations in the CF transmembrane conductance regulator (CFTR) gene
   • Abnormal nasal potential difference (NPD) with accompanying symptoms characteristic of CF

3. Chronic infection with Burkholderia spp. defined by:

   • One sputum (or bronchoalveolar lavage) culture positive for Burkholderia spp. within 6 months prior to baseline assessment,
   • At least 50% of sputum (or bronchoalveolar lavage) cultures collected at least one month apart over the previous 12 months prior to baseline assessment positive for Burkholderia spp. (minimum of 2 positive cultures), and
   • At least one positive sputum (or bronchoalveolar lavage) culture (obtained at any point in time) confirmed to be Burkholderia spp. by the Cystic Fibrosis Foundation (CFF) Burkholderia cepacia Research Laboratory and Repository at the University of Michigan (or equivalent Canadian reference laboratory).
4. Concomitant aerosolized antibiotic treatment: subjects receiving intermittent (alternating month on/month off) aerosolized antibiotic treatment were eligible, but must have been at least 1 week into their off-treatment cycle at the time of baseline assessment. Subjects receiving continuous aerosolized antibiotic treatment were eligible without restriction on their aerosolized antibiotic treatment.
5. Chest radiograph, computed tomography (CT), or magnetic resonance imaging (MRI) (most recent, obtained within 90 days of screening) without significant acute findings (eg, infiltrates [lobar or diffuse interstitial], pleural effusion, pneumothorax), and no significant intercurrent illness; chronic, stable findings (eg, chronic scarring or atelectasis) were allowed.
6. Subjects (and parent/guardian as required) must have been able to provide written informed consent/assent prior to any study-related procedures,
7. Ability to perform reproducible pulmonary function tests
8. Sexually active females of childbearing potential must have agreed to use a highly effective method of contraception during heterosexual intercourse throughout the study period and for 30 days following discontinuation of study drug. A highly effective method of birth control was defined as a method that would result in a low failure rate (ie, less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), or a vasectomized partner.

Exclusion Criteria:

1. Administration of any investigational drug or use of any investigational device within 28 days of randomization/baseline and within six half-lives of the investigational drug (whichever is longer)
2. Administration of AZLI treatment within the 28 days prior to randomization/baseline
3. Known local or systemic hypersensitivity to monobactam antibiotics
4. History of lung transplantation

5. Abnormal renal or hepatic function results at most recent test within the previous 90 days, defined as:

   • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times the upper limit of the normal range (ULN)
   • Serum creatinine > 2 times ULN
6. Known portal hypertension or complications of CF hepatopathy
7. Positive urine pregnancy test (confirmed by serum pregnancy test) at screening; all women of childbearing potential were tested
8. Any female of childbearing potential who was lactating or not practicing a highly effective method of birth control as defined in the protocol
9. Any serious or active medical or psychiatric illness which, in the opinion of the investigator, would have interfered with subject treatment, assessment or compliance with the protocol

Contacts and Locations

Locations

United States, Alabama

Mobile, Alabama, United States, 36608

United States, Arizona

Phoenix, Arizona, United States, 85016

United States, Arkansas

Little Rock, Arkansas, United States, 72205

United States, Colorado

Denver, Colorado, United States, 80206

United States, Connecticut

Hartford, Connecticut, United States, 06102

United States, Delaware

Wilmington, Delaware, United States, 19803

United States, Florida

Jacksonville, Florida, United States, 32207

Miami, Florida, United States, 33136

Tampa, Florida, United States, 33606

United States, Illinois

Glenview, Illinois, United States, 60025

United States, Massachusetts

Boston, Massachusetts, United States, 02115

Worcester, Massachusetts, United States, 01605

United States, Michigan

Detroit, Michigan, United States, 48201

United States, Minnesota

Minneapolis, Minnesota, United States, 55455

United States, Missouri

St. Louis, Missouri, United States, 63110

United States, Nevada

Las Vegas, Nevada, United States, 89107

United States, New Jersey

Morristown, New Jersey, United States, 07962

New Brunswick, New Jersey, United States, 08903

United States, New Mexico

Albuquerque, New Mexico, United States, 87131

United States, New York

New Hyde Park, New York, United States, 11040

United States, North Carolina

Chapel Hill, North Carolina, United States, 27599

United States, Ohio

Akron, Ohio, United States, 44308

Columbus, Ohio, United States, 43205

Toledo, Ohio, United States, 43606

United States, Oklahoma

Oklahoma City, Oklahoma, United States, 73112

United States, Oregon

Portland, Oregon, United States, 97239

United States, Pennsylvania

Hershey, Pennsylvania, United States, 17033

Philadelphia, Pennsylvania, United States, 19104

Pittsburgh, Pennsylvania, United States, 15201

United States, South Carolina

Charleston, South Carolina, United States, 29425

Columbia, South Carolina, United States, 29203

United States, Virginia

Richmond, Virginia, United States, 23298

United States, West Virginia

Morgantown, West Virginia, United States, 26506

United States, Wisconsin

Milwaukee, Wisconsin, United States, 53201

Canada, Ontario

Toronto, Ontario, Canada, M5B 1W8

Sponsors and Collaborators

Gilead Sciences

Investigators

• Study Director: Mark Bresnik, MD; Gilead Sciences

More Information

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT01059565
• Other Study ID Numbers: GS-US-205-0127
• First Posted: February 1, 2010
• Results First Posted: March 11, 2014
• Last Update Posted: March 11, 2014
• Last Verified: February 2014

Keywords provided by Gilead Sciences:

Cystic Fibrosis; Aztreonam Lysine; lung infection; Burkholderia; CFQ-R; inhaled antibiotic

Additional relevant MeSH terms:

Infections; Communicable Diseases; Burkholderia Infections; Cystic Fibrosis; Fibrosis; Disease Attributes; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses