Cystic Fibrosis


Table 4: Incidence of Adverse Drug Reactions per Patient-Month


Number of Occurrences per Patient-Montha Pooled AIR-CF1 and AIR-CF (Placebo Controlled)


Placebo (n=160)


Preferred Termb


275 Patient- Months


Cough 0.356 Nasal congestion 0.073 Pyrexia 0.036 Wheezing 0.065 Pharyngolaryngeal 0.062 pain


Chest discomfort 0.040 Abdominal paind Rhinorrhoeae Vomitingd


0.029 0.040 0.025


Rash 0.011


dividing by 28. b


AZLIc (n=215)


442 Patient- Months


0.387 0.097 0.088 0.072 0.068


0.059 0.041 0.041 0.032 0.009


AIR-CF3


(Open Label) AZLIc


(n=274)


4128 Patient- Months


0.279 0.045 0.055 0.029 0.051


0.032 0.013 0.034 0.021 0.007


aPatient-months were calculated by adding up study duration (days) for all patients and


Adverse events were coded with the Medical Dictionary for Regulatory Activities, Version 8.0 and are displayed by decreasing incidence for AZLI-treated patients in the


placebo-controlled studies. c


product characteristics.11 e


Includes patients receiving AZLI BID or TID. dNot included in the list of common adverse reactions in the European summary of


Not included in the list of common adverse reactions in the US prescribing information.13 AZLI = aztreonam for inhalation solution.


The CFQ-R RSS treatment effect (AZLI–placebo) at day 28 was 6.7 points


(p=0.07) for patients with baseline FEV1 <90 % predicted and was -1.4 points (p=0.66) for patients with baseline FEV1 ≥90 % predicted. The FEV1 % predicted treatment effect (AZLI-placebo) at day 28 was 4.8 % (p=0.03) for patients with baseline FEV1 <90 % predicted and was 1.4 % (p=0.30) for patients with baseline FEV1 ≥90 % predicted.


averaged 1.8 courses for patients in this trial. After 28 days of dosing, AZLI versus placebo treatment differences favoured AZLI, and were 9.7


points on the CFQ-R RSS, 10.3% for FEV1 (L), and -1.45 log10 PA CFU/g sputum (each p<0.001). The minimal important difference (MID) on the CFQ-R RSS is 4 points, favouring the interpretation that the observed improvement in respiratory symptoms was both statistically significant and clinically meaningful to patients.29


AIR-CF2 (CP-AI-005) This Phase III trial assessed AZLI 75 mg versus placebo in patients


with FEV1 ≤75 % and ≥25 % predicted (see Table 3). Study drug was administered BID or TID for 28 days and patients were then followed for 56 days.26


TNS use in the previous 12 months averaged


5.3 courses; thus, patients were receiving more ongoing treatment with aerosolised antibiotics than the patients in AIR-CF1. Further, all patients received TNS 300 mg BID for 28 days immediately prior to the AZLI/placebo treatment period. Median time to need for additional antipseudomonal antibiotics to treat symptoms of pulmonary exacerbation was significantly longer for AZLI-treated than for placebo-treated patients (p=0.007). After 28 days of dosing; AZLI versus placebo treatment differences favoured AZLI, and were


5.01 points on the CFQ-R RSS (p=0.02), 6.3 % for FEV1 (L) (p=0.001), and -0.66 log10 PA CFU/g sputum (p=0.006). AIR-CF3 (CP-AI-006)


This open-label, Phase III follow-on study enrolled patients from AIR-CF1 and AIR-CF2, and assessed up to nine 28 day courses of AZLI 75 mg, administered BID or TID (see Table 3). Each course was separated by 28 days off-treatment.32


During each course, CFQ-R


RSS, FEV1 (L), and FEV1 % predicted improved, and log10 PA CFU/g sputum decreased. Responses were better following TID dosing


than after BID dosing. During off-treatment periods, treatment 120 Other Clinical Studies


A recently completed Phase IIIb study assessed AZLI 75 mg TID versus placebo in patients with CF and chronic Burkholderia species infection (see Table 3).37


Inhaled antibiotics for patients with CF


A pilot study is assessing efficacy and antibiotic resistance after treating patients with intermittent courses of AZLI or TNS, or continuous alternating courses of AZLI and TNS.42 being assessed for treatment of non-CF bronchiectasis.43-44


are increasingly used in rotation, with a 28-day course of one antibiotic alternating with a 28-day course of a second antibiotic.38 A course of AZLI showed good efficacy when combined with a course of fosfomycin/tobramycin for inhalation (FTI) in a recent Phase II clinical trial.39–41


AZLI is also Safety and Tolerability


AZLI was well tolerated and adverse events reported during the clinical trials were generally consistent with CF lung disease. Cough and productive cough were the adverse events with highest incidence in each of the Phase III trials. After reviewing the data from AIR-CF1 and AIR-CF2, 10 events were considered adverse drug reactions (see Table 4). These events were selected because the relationship with use of AZLI was considered biologically plausible or the events were reported with higher incidence in the AZLI treatment arm than in the placebo arm. In AIR-CF1 and AIR-CF2, the incidence of pyrexia was significantly higher


EUROPEAN RESPIRATORY DISEASE


Aztreonam for Inhalation Solution versus Tobramycin Nebuliser Solution Active Comparator Study This recently completed Phase III study assessed three 28-day courses of AZLI 75mg TID versus TNS 300 mg BID in patients with FEV1 ≤75 % (see Table 3).34–36


Each course was separated by 28 days


off-treatment. The comparative phase was followed by an optional open-label, single arm, European, extension study that evaluated the safety and efficacy of AZLI for three additional treatment cycles.


responses declined, but generally remained above baseline values for patients dosed with AZLI TID. During the 18-month


study, the MIC50 of aztreonam for PA remained unchanged (±2-fold change) from baseline and only transient increases in MIC90 were observed.


AIR-CF4 This Phase III study assessed AZLI 75 mg versus placebo in patients


Enrollment of patients with less severe lung disease resulted in the inclusion of more paediatric patients than had been enrolled in Phase III clinical trials described above. After 28 days of dosing, AZLI versus placebo treatment differences favoured AZLI, and


with FEV1 >75 % predicted (see Table 3). Study drug was administered TID for 28 days.33


were 1.8 points on the CFQ-R RSS (p=0.44), 2.7 % for FEV1 % predicted (p=0.02) and -1.2 log10 PA CFU/g sputum (p=0.02). Although the study did not meet the primary efficacy end-point (CFQ-R RSS), pulmonary


function improved and bacterial density decreased in these patients with mild CF disease. Further, patients with FEV1 <90 % predicted had


larger treatment effects favoring AZLI than patients with baseline FEV1 ≥90 % predicted.


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