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Safety and Efficacy Study of Aztreonam for Inhalation Solution (AZLI) in Cystic Fibrosis (CF) Patients With Pseudomonas Aeruginosa (PA) (AIR-CF3)

Primary Purpose

Cystic Fibrosis

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

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

About this trial

This is an interventional treatment trial for Cystic Fibrosis focused on measuring cystic fibrosis, Pseudomonas aeruginosa

Eligibility Criteria

6 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 Completion of CP-AI-005 or CP-AI-007 or was withdrawn due to need for antipseudomonal antibiotics or for an AE unrelated to study medication tolerance.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

Sites / Locations

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

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.

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.

Serum Hematology - Concentration of White Blood Cells (WBC), Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, and Platelets

Serum Hematology - Percent of Differential for Basophils, Eosinophils, Lymphocytes, Monocytes, and Neutrophils

Serum Hematology - Number of Red Blood Cells (RBC)

Serum Hematology - Hematocrit

Serum Hematology - Hemoglobin

Serum Hematology - Mean Corpuscular Volume (MCV)

Serum Hematology - Mean Corpuscular Hemoglobin (MCH)

Serum Hematology - Mean Corpuscular Hemoglobin Concentration (MCHC)

Serum Chemistry - Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), and Gamma-glutamlytransferase (GGT)

Serum Chemistry - Concentration of Calcium, Creatinine, Direct Bilirubin, Total Bilirubin, Serum Glucose, and Blood Urea Nitrogen

Serum Chemistry - Concentration of Chloride, Potassium, and Sodium

Serum Chemistry - Concentration of Total Protein

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT00128492

First Posted

August 8, 2005

Last Updated

May 17, 2011

Sponsor

Gilead Sciences

1. Study Identification

Unique Protocol Identification Number

NCT00128492

Brief Title

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

Acronym

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)

Study Type

Interventional

2. Study Status

Record Verification Date

May 2011

Overall Recruitment Status

Completed

Study Start Date

August 2005 (undefined)

Primary Completion Date

November 2008 (Actual)

Study Completion Date

January 2009 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor

Gilead Sciences

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief 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).

Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cystic Fibrosis

Keywords

cystic fibrosis, Pseudomonas aeruginosa

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

274 (Actual)

8. Arms, Groups, and Interventions

Intervention Type

Drug

Intervention Name(s)

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

Primary Outcome Measure Information:

Title

Number of Participants Reporting Adverse Events (AEs)

Description

Time Frame

Overall study (72 weeks) included nine 28-day courses of study drug alternating with nine 28-day courses off drug

Title

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

Description

Time Frame

Overall study (72 weeks) included nine 28-day courses of study drug alternating with nine 28-day courses off drug

Title

Change in Heart Rate (HR)

Description

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.

Time Frame

Baseline, and end of treatment Courses 1 (Week 4), 3 (Week 20) and 9 (Week 68)

Title

Change in Systolic and Diastolic Blood Pressure (BP)

Description

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.

Time Frame

Baseline, and end of treatment Courses 1 (Week 4), 3 (Week 20) and 9 (Week 68)

Title

Change in Temperature

Description

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.

Time Frame

Baseline, and end of treatment Courses 1 (Week 4), 3 (Week 20) and 9 (Week 68)

Title

Change in Respiratory Rate (RR)

Description

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.

Time Frame

Baseline, and end of treatment Courses 1 (Week 4), 3 (Week 20) and 9 (Week 68)

Title

Serum Hematology - Concentration of White Blood Cells (WBC), Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, and Platelets

Time Frame

Baseline and end of Course 9 (Week 68)

Title

Serum Hematology - Percent of Differential for Basophils, Eosinophils, Lymphocytes, Monocytes, and Neutrophils

Time Frame