A phase 1 randomized, double-blind, placebo-controlled, crossover trial of DAS181 (Fludase®) in adult subjects with well-controlled asthma

Abstract

Background: Influenza virus (IFV) infection is associated with increased morbidity and mortality in people with underlying lung disease. Treatment options for IFV are currently limited and antiviral resistance is a growing concern. DAS181, an inhaled antiviral with a unique mechanism of action, has shown promise in early clinical trials involving generally healthy human subjects. This study was undertaken to assess the safety and tolerability of DAS181 in individuals with underlying reactive airway disease.

Methods: This was a randomized, double-blind, placebo-controlled, crossover phase 1 study of DAS181-F02. Dry particle inhaler administration of 10 mg was done on 3 consecutive days in ten adult volunteers with well-controlled asthma. The primary outcome was the frequency of adverse events (AEs), grade 1 or higher that occurred during each study period.

Results: There were 280 AEs among ten evaluable subjects (56.8 % active; 43.2 % placebo); 90.7 % were grade 1. No grade 3 or higher AEs occurred. A statistically significant association between exposure to DAS181 and experiencing any AE, a grade 1 AE, or a grade 2 AE was not detected. Overall, the majority of AEs were classified as possibly related (35.7 %), unlikely related (38.9 %), or unrelated (15.4 %) to study drug administration. However, there was a statistically significant association between exposure to DAS181 and experiencing a definitely or probably related AE. Respiratory effects, including dyspnea, dry cough, and chest discomfort related to respirations, accounted for all of the definitely related AEs and one of the most common probably related AEs.

Conclusions: DAS181 was safe in this small study of otherwise healthy subjects with well-controlled asthma. However, the generalizability of these results is limited by the small sample size and generally mild nature of the subjects' asthma at baseline. The increased association of respiratory events classified as probably or definitely related to DAS181 administration suggests caution may need to be employed when administering DAS181 to individuals with less stable reactive airway disease. Further investigation in a controlled setting of the safety and efficacy of DAS181 in a larger population of asthmatic subjects with varying disease activity is warranted.

Trial registration: ClinicalTrials.gov NCT01113034 Trial Registration Date: April 27, 2010.

Fig. 1

Schematic of study design. Subjects who met eligibility criteria during screening were randomized to receive three consecutive daily doses of either DAS 181 or placebo starting on day 0, the first day of the initial period. Subjects were evaluated at specified time-points for an additional 18 days, then crossed-over to the other treatment group within 6 weeks of completing the initial period. Abbreviations: I = initial; CO = crossover

Fig. 2

Flow chart depicting reasons for exclusion of subjects and adverse events from final analysis. Half of the 22 screened subjects failed to meet inclusion or exclusion criteria. One enrolled subject withdrew after the initial period thus his data was excluded from the final analysis according to protocol. Adverse events that occurred before dosing or between periods were also excluded. Ultimately, ten subjects accounted for 280 adverse events in the final analysis. Abbreviations: AEs = adverse events

Fig. 3

Distribution of adverse events by grade and relatedness, according to study period. Of the 280 total AEs, 56.8 % occurred during the active period and 43.2 % during the placebo period. 254 (90.7 %) AEs were grade 1 and 26 (9.3 %) grade 2. While only 28 (10 %) AEs were classified as definitely or probably related, all 28 occurred during the active period, representing a statistically significant association between exposure to DAS181 and experiencing a definitely or probably related AE (8 discordant pairs, exact test p = 0.0039)

Fig. 4

Distribution of most common adverse event types by study period and grade. The respiratory symptoms depicted in this figure accounted for 99 adverse events and represented four of the most common adverse events overall. The variable depicted as “Cough (all types)” included all cough related AEs including dry cough, cough not otherwise specified, and productive cough. The majority of AEs were grade 1, however all grade 2 AEs in this group occurred during the active period

Fig. 5

Percent (%) change in post-dose FEV1 compared to pre-dose, by dosing day. The change in median FEV1 following DAS181 versus placebo dosing was not statistically different either overall (p = 0.45) or by dosing day