Safety and Efficacy Study of Aztreonam for Inhalation Solution (AZLI) in Cystic Fibrosis (CF) Patients With Pseudomonas Aeruginosa (PA)

Cystic Fibrosis Clinical Trial

— AIR-CF3  

Official title:

A Phase 3, Open-label, Follow-On Study of Multiple Courses of Aztreonam Lysinate for Inhalation (AI) in Cystic Fibrosis Patients (AIR-CF3)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00128492
• Other study ID #: CP-AI-006
• Status: Completed
• Phase: Phase 3
• First received: August 8, 2005
• Last updated: May 17, 2011
• Start date: August 2005
• Est. completion date: January 2009

Study information

• Verified date: May 2011
• 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 study was to evaluate the safety and efficacy of multiple courses of AZLI in patients with cystic fibrosis (CF) and lung infection due to Pseudomonas aeruginosa (PA).

Description:

People with CF often have lung infections that occur repeatedly or worsen over time. The lung infections are often caused by PA. Treatment with antibiotics is used to reduce the presence of the bacteria. The antibiotics may be given orally, intravenously, or inhaled as a mist. The purpose of this study was to evaluate whether AZLI, an investigational formulation of the antibiotic aztreonam, is safe in repeated courses in patients with CF and PA.

A course of AZLI treatment in this study comprised 28 days, followed by a 28-day period off treatment. Participants could receive up to 9 courses of AZLI, with a total time on study of up to 18 months. Safety and efficacy results for the 18-month, 9-course period are reported, with efficacy results presented on a by-treatment course basis.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 274
• Est. completion date: January 2009
• Est. primary completion date: November 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Years and older

Eligibility

Inclusion Criteria:

• Compliance with Studies CP-AI-005 (NCT00104520) or CP-AI-007 (NCT00112359) by taking at least 50% of expected study medication.

• Completion of CP-AI-005 or CP-AI-007 or was withdrawn due to need for antipseudomonal antibiotics or for an AE unrelated to study medication tolerance.

• Ability to provide written informed consent/assent prior to initiation of study-related procedures.

• Ability to perform reproducible pulmonary function tests.

Exclusion Criteria:

• Use of any investigational medication or device between the last visit of CP-AI-005 or CP-AI-007 and Visit 1 of this study.

• Concurrent participation in a study of another investigational drug or device.

• Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone/day or 20 mg prednisone every other day.

• History of sputum or throat swab culture yielding Burkholderia cepacia in the previous 2 years.

• History of daily continuous oxygen supplementation or requirement for more than 2 liters/minute at night.

• Inability to tolerate study medication in CP-AI-005 or CP-AI-007.

• Known local or systemic hypersensitivity to aztreonam.

• Inability to tolerate inhalation of a short acting beta-2 agonist.

• Abnormal renal or hepatic function based on results of most recent test.

• Female of child-bearing potential who was pregnant, lactating, or not (in the opinion of the investigator) practicing an acceptable method of birth control.

• Any serious or active medical or psychiatric illness which, in the opinion of the investigator, would have interfered with participant treatment, assessment, or compliance with the protocol.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Drug:
• AZLI 75 mg two times a day (BID)/ three times a day (TID)

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Australia,  Canada,  New Zealand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Reporting Adverse Events (AEs)	Participants experiencing at least 1 treatment-emergent AE or at least 1 serious adverse event (SAE) were summarized for the study as a whole. A treatment-emergent AE was any physical or clinical worsening in symptoms or disease experienced by the participant, whether or not the event was considered related to study participation or study procedures. An SAE was any adverse experience that resulted in hospitalization or death.; Participants were monitored for AEs and SAEs during all on-treatment and off-treatment intervals throughout the 18-month study period.	Overall study (72 weeks) included nine 28-day courses of study drug alternating with nine 28-day courses off drug	Yes
Primary	Number of Subjects With <15% or =15% Decline in Forced Expiratory Volume in 1 Second [FEV1] From Pretreatment to 30 Minutes After Treatment With AZLI	Airway reactivity (percent change in FEV1 from pretreatment to 30 minutes after treatment with AZLI) was assessed at all study visits in which a participant received AZLI treatment. A participant was included in this endpoint if they experienced a decline in FEV1 of =15% at any visit in which they received AZLI.	Overall study (72 weeks) included nine 28-day courses of study drug alternating with nine 28-day courses off drug	Yes
Primary	Change in Heart Rate (HR)	HR was recorded at all visits.; Change from baseline at the end of AZLI treatment Courses 1 (Visit 2), 3 (Visit 4), and 9 (Visit 19) was determined.	Baseline, and end of treatment Courses 1 (Week 4), 3 (Week 20) and 9 (Week 68)	Yes
Primary	Change in Systolic and Diastolic Blood Pressure (BP)	BP was recorded at all visits.; Change from baseline at the end of AZLI treatment Courses 1 (Visit 2), 3 (Visit 4), and 9 (Visit 19) was determined.	Baseline, and end of treatment Courses 1 (Week 4), 3 (Week 20) and 9 (Week 68)	Yes
Primary	Change in Temperature	Temperature was recorded at all visits.; Change from baseline at the end of AZLI treatment Courses 1 (Visit 2), 3 (Visit 4), and 9 (Visit 19) was determined.	Baseline, and end of treatment Courses 1 (Week 4), 3 (Week 20) and 9 (Week 68)	Yes
Primary	Change in Respiratory Rate (RR)	RR was recorded at all visits.; Change from baseline at the end of AZLI treatment Courses 1 (Visit 2), 3 (Visit 4), and 9 (Visit 19) was determined.	Baseline, and end of treatment Courses 1 (Week 4), 3 (Week 20) and 9 (Week 68)	Yes
Primary	Serum Hematology - Concentration of White Blood Cells (WBC), Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, and Platelets		Baseline and end of Course 9 (Week 68)	Yes
Primary	Serum Hematology - Percent of Differential for Basophils, Eosinophils, Lymphocytes, Monocytes, and Neutrophils		Baseline and end of treatment Course 9 (Week 68)	Yes
Primary	Serum Hematology - Number of Red Blood Cells (RBC)		Baseline and end of treatment Course 9 (Week 68)	Yes
Primary	Serum Hematology - Hematocrit		Baseline and end of treatment Course 9 (Week 68)	Yes
Primary	Serum Hematology - Hemoglobin		Baseline and end of treatment Course 9 (Week 68)	Yes
Primary	Serum Hematology - Mean Corpuscular Volume (MCV)		Baseline and end of treatment Course 9 (Week 68)	Yes
Primary	Serum Hematology - Mean Corpuscular Hemoglobin (MCH)		Baseline and end of treatment Course 9 (Week 68)	Yes
Primary	Serum Hematology - Mean Corpuscular Hemoglobin Concentration (MCHC)		Baseline and end of treatment Course 9 (Week 68)	Yes
Primary	Serum Chemistry - Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), and Gamma-glutamlytransferase (GGT)		Baseline and end of treatment Course 9 (Week 68)	Yes
Primary	Serum Chemistry - Concentration of Calcium, Creatinine, Direct Bilirubin, Total Bilirubin, Serum Glucose, and Blood Urea Nitrogen		Baseline and end of treatment Course 9 (Week 68)	Yes
Primary	Serum Chemistry - Concentration of Chloride, Potassium, and Sodium		Baseline and end of treatment Course 9 (Week 68)	Yes
Primary	Serum Chemistry - Concentration of Total Protein		Baseline and end of treatment Course 9 (Week 68)	Yes
Secondary	Change From Baseline in Pseudomonas Aeruginosa (PA) log10 Colony-forming Units (CFU) Per Gram of Sputum	Sputum samples were collected at all participant visits of the study for analysis of microbiology endpoints. Sputum samples were processed for qualitative and quantitative culture of PA (each morphotype).; Due to the skewness of the distribution of CFU data, the data were transformed using the base 10 logarithm, in an attempt to normalize the data and allow for parametric tests, before calculating changes. To account for zero values, 1 was added to each CFU measurement before being transformed. Any CFU data values where PA was not isolated from a valid culture were set to zero.	Baseline, and the end of treatment Courses 1 (Week 4), 3 (Week 20), and 9 (Week 68)	No
Secondary	Number of Participants With Other Pathogens	Sputum samples were collected at all study visits for qualitative and quantitative culture for Burkholderia cepacia complex (BCC), Stenotrophomonas maltophilia, Achromobacter xylosoxidans, Staphylococcus aureus (including methicillin-sensitive [MSSA] and methicillin-resistant [MRSA] S.aureus), and fungal organisms.; Number of participants with other pathogens at baseline and end of AZLI treatment Courses 1, 3, and 9 are reported.	Baseline; end of treatment Courses 1 (Week 4), 3 (Week 20), and 9 (Week 68); and at Follow-up (Week 72)	Yes
Secondary	Minimum Inhibitory Concentration (MIC) of Aztreonam	The aztreonam susceptibility of PA isolates from expectorated sputum samples (collected at all visits) was assessed.; MIC50 = minimum inhibitory concentration (minimum concentration of an agent that inhibits 50% of isolates from a particular organism).; MIC90 = minimum inhibitory concentration (minimum concentration of an agent that inhibits 90% of isolates from a particular organism).; MIC50 and MIC90 values are single measurements for the entire population and not measured on a per-participant basis.	Baseline; end of treatment Courses 1 (Week 4), 3 (Week 20), and 9 (Week 68); and at Follow-up (Week 72)	Yes
Secondary	Percent Change in Pulmonary Function (FEV1, FEV1 Percent Predicted, FVC, FEF25-75)	Spirometry was performed at each visit. FEV1, FVC, and FEF25-75 were recorded at all visits according to American Thoracic Society (ATS) guidelines.; FEV1 = the volume of air exhaled in 1 second. FEV1 % predicted is a normalized value of FEV1 calculated using the Knudson equation, based upon participant age, gender, and height. FVC = (forced vital capacity) the maximal volume of air exhaled with maximally forced effort from a position of maximal inspiration. FEF25-75 = forced expiratory flow from 25% to 75% of the FVC.; The percent change from baseline is presented for each endpoint.	Baseline, and end of treatment Courses 1 (Week 4), 3 (Week 20), and 9 (Week 68)	No
Secondary	Change in Clinical Symptoms as Assessed by the Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Scale (CFQ-R RSS)	The CFQ-R was administered at baseline and every visit thereafter. The endpoint was change in respiratory symptoms from baseline, assessed with the CFQ-R RSS (range of scores: 0-100; higher scores indicate fewer symptoms). The minimal clinically important difference (MCID) corresponds to the smallest change in symptoms that a patient can detect and is a change in score of 4 points.	Baseline, and end of treatment Courses 1 (Week 4), 3 (Week 20), and 9 (Week 68)	No
Secondary	Time to First Hospitalization Due to a Respiratory Event	Details of all hospitalizations, including the dates of admission and discharge, were recorded on the serious adverse event (SAE) electronic case report form (eCRF).; Time to first hospitalization was the number of days from baseline (Visit 1) to the date of first hospitalization or the date of study completion (last visit) /or early withdrawal if censored.	Overall study (72 weeks) included nine 28-day courses of study drug alternating with nine 28-day courses off drug	No
Secondary	Change in Body Weight	Weight was measured at all visits and was reported to the nearest 0.1 kg/lb. Percent change in weight from baseline was calculated.	Baseline, and end of treatment Courses 1 (Week 4), 3 (Week 20), and 9 (Week 68)	No
Secondary	Missed School/Work Days Due to CF Symptoms	Participants were provided with a diary card at each visit to record days of work and/or school missed due to their CF symptoms.; The percentage of school/work days missed was calculated as the total number of school/work days missed divided by the total number of on-study days multiplied by 100 across all participants in a treatment group.	Overall study (72 weeks) included nine 28-day courses of study drug alternating with nine 28-day courses off drug	No
Secondary	Time to Intravenous (IV) Antipseudomonal Antibiotics	Use of IV antipseudomonal antibiotics was compiled from data recorded on the Concomitant Medications eCRF. The time to first IV antipseudomonal antibiotic use was the number of days from baseline (Visit 1) to the date of first IV antipseudomonal antibiotic use or the date of study completion (last visit) /or early withdrawal if censored.	Overall study (72 weeks) included nine 28-day courses of study drug alternating with nine 28-day courses off drug	No