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

Cystic Fibrosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01059565
• Other study ID #: GS-US-205-0127
• Status: Completed
• Phase: Phase 3
• First received: January 28, 2010
• Last updated: February 7, 2014
• Start date: February 2010
• Est. completion date: January 2012

Study information

• Verified date: February 2014
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 102
• Est. completion date: January 2012
• Est. primary completion date: September 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Burkholderia Infections
• Communicable Diseases
• Cystic Fibrosis
• Fibrosis
• Infection

Intervention

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
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.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	AUCave of Relative Change in FEV1 % Predicted From 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.	Baseline to Week 24	No
Secondary	Total Number of Systemic and/or Inhaled Antibiotic Courses for Respiratory Events	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.	Baseline to Week 24	No
Secondary	AUCave of Change in CFQ-R RSS Scores From 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.	Baseline to Week 24	No
Secondary	AUCave of Relative Change From Baseline to Week 24 in FEV1	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.	Baseline to Week 24	No
Secondary	AUCave of Relative Change From Baseline to Week 24 in FVC	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.	Baseline to Week 24	Yes
Secondary	AUCave of Relative Change From Baseline to Week 24 in FEF25-75	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.	Baseline to Week 24	Yes
Secondary	AUCave of the Change From Baseline to Week 24 in Physical Functioning Score as Assessed by the CFQ-R	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.	Baseline to Week 24	No
Secondary	AUCave of the Change From Baseline to Week 24 in Weight Score as Assessed by the CFQ-R	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.	Baseline to Week 24	No
Secondary	AUCave of the Change From Baseline to Week 24 in Treatment Burden Score as Assessed by the CFQ-R	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.	Baseline to Week 24	No
Secondary	Change in BMI From Baseline to Week 24	The change in BMI from baseline to Week 24 was analyzed.	Baseline to Week 24	No
Secondary	Change in Burkholderia Spp. CFU in Sputum From Baseline to Week 24	The change in Burkholderia spp. CFU in sputum from baseline to Week 24 was analyzed.	Baseline to Week 24	No
Secondary	Percentage of Days Participants Used Antibiotics	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.	Baseline to Week 24	No
Secondary	Percent of Days Hospitalized	The percentage of days hospitalized from baseline to Week 24 was analyzed.	Baseline to Week 24	No
Secondary	Percentage of Missed School or Work Days	The percentage of days participants missed school or work from baseline to Week 24 was analyzed.	Baseline to Week 24	No