Treatment of Aspergillus fumigatus in patients with cystic fibrosis: a randomized, placebo-controlled pilot study

Shawn D Aaron, Katherine L Vandemheen, Andreas Freitag, Linda Pedder, William Cameron, Annick Lavoie, Nigel Paterson, Pearce Wilcox, Harvey Rabin, Elizabeth Tullis, Nancy Morrison, Felix Ratjen, Shawn D Aaron, Katherine L Vandemheen, Andreas Freitag, Linda Pedder, William Cameron, Annick Lavoie, Nigel Paterson, Pearce Wilcox, Harvey Rabin, Elizabeth Tullis, Nancy Morrison, Felix Ratjen

Abstract

Background: Many patients with cystic fibrosis develop persistent airway infection/colonization with Aspergillus fumigatus, however the impact of A. fumigatus on clinical outcomes remains unclear. The objective of this study was to determine whether treatment directed against Aspergillus fumigatus improves pulmonary function and clinical outcomes in patients with cystic fibrosis (CF).

Methods: We performed a double-blind randomized placebo-controlled pilot clinical trial involving 35 patients with CF whose sputum cultures were chronically positive for A. fumigatus. Participants were centrally randomized to receive either oral itraconazole 5 mg/kg/d (N = 18) or placebo (N = 17) for 24 weeks. The primary outcome was the proportion of patients who experienced a respiratory exacerbation requiring intravenous antibiotics over the 24 week treatment period. Secondary outcomes included changes in FEV(1) and quality of life.

Results: Over the 24 week treatment period, 4 of 18 (22%) patients randomized to itraconazole experienced a respiratory exacerbation requiring intravenous antibiotics, compared to 5 of 16 (31%) placebo treated patients, P = 0.70. FEV(1) declined by 4.62% over 24 weeks in the patients randomized to itraconazole, compared to a 0.32% improvement in the placebo group (between group difference = -4.94%, 95% CI: -15.33 to 5.45, P = 0.34). Quality of life did not differ between the 2 treatment groups throughout the study. Therapeutic itraconazole blood levels were not achieved in 43% of patients randomized to itraconazole.

Conclusion: We did not identify clinical benefit from itraconazole treatment for CF patients whose sputum was chronically colonized with A. fumigatus. Limitations of this pilot study were its small sample size, and failure to achieve therapeutic levels of itraconazole in many patients.

Trial registration: ClinicalTrials.gov NCT00528190.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Trial Profile.
Figure 1. Trial Profile.
Figure 2. Time to First Pulmonary Exacerbation…
Figure 2. Time to First Pulmonary Exacerbation Requiring Oral or Intravenous Antibiotics.
Blue dashed line = placebo-treated patients. Black solid line = itraconazole-treated patients. The median time to first exacerbation was 77 days for the itraconazole group and 134 days for the placebo group, log-rank P = 0.35. Hash marks = censored observations.
Figure 3. Changes from Baseline in FEV1…
Figure 3. Changes from Baseline in FEV1 Over the 48-Week Study.
Blue dashed line = placebo-treated patients. Black solid line = itraconazole-treated patients. 95% confidence intervals are indicated by the error bars around the mean values.

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Source: PubMed

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