The reproducibility of adenosine monophosphate bronchial challenges in mild, steroid-naive asthmatics

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Repeated adenosine monophosphate (AMP) challenges are used to assess drug effects in asthma clinical trials, but may be prone to tachyphylaxis when repeated at short intervals. • Possible tachyphylaxis at 12- and 24-h intervals has not been studied. WHAT THIS STUDY ADDS • Clinically relevant tachyphylaxis after repeated AMP challenges does not occur when repeated at 12- and 24-h intervals. • AMP challenges at these intervals can be used to assess drug effects in clinical trials. AIMS Repeated adenosine monophosphate (AMP) challenges are used to assess drug efficacy in clinical trials of mild, steroid-naive asthmatics. Refractoriness has been reported after repeated challenges over short intervals. This study evaluated possible tachyphylaxis after repeated AMP challenges at 12 and 24 h in mild, steroid-naive asthmatics. METHODS This was an open, three-way crossover study. Twenty-six steroid-naive asthmatic subjects were randomized to the following AMP challenge regimens separated by 7–14 days: (A) challenge at 08.00 h, repeated 24 h later; (B) challenge at 08.00 h, repeated 12 and 24 h later; (C) challenge at 20.00 h, repeated 12 h later. Comparisons within day were assessed using 90% confidence intervals (CIs). Non-inferiority approach taken with 1 doubling concentration (DC) as a clinically relevant difference. RESULTS Regimen A: Significant increase in AMP reactivity at 24 h. Mean DC difference was 0.6 (90% CI 0.24, 0.96). Regimen B: No evidence of difference between AMP reactivity at 08.00 h and a repeated challenge 12 h later. Repeated challenge at 24 h caused a significant increase in provocation concentration (PC)20 compared with 12 h (mean DC difference 0.48, 90% CI 0.02, 0.95) and 0 h (mean DC difference 0.82, 90% CI 0.49, 1.14 – the upper CI exceeds the criteria of 1 DC). Challenge regimen C: No difference between challenges; mean DC difference of 0.28 (90% CI −0.2, 0.76). CONCLUSION The small decline in AMP reactivity during repeated challenges was not consistently observed, and was small compared with the known effects of inhaled drugs.