The average Adjusted Symptom Score, a new primary efficacy end-point for specific allergen immunotherapy trials

Background In clinical trials, the efficacy of immunotherapy for allergic rhinoconjunctivitis symptoms is often evaluated with the average Rhinoconjunctivitis Total Symptom Score (ARTSS). Effective treatment is associated with a lower ARTSS vs. placebo but use of rescue medication to alleviate symptoms reduces the RTSS and decreases the mean difference between active treatment and placebo groups. Objective To develop and describe the average Adjusted Symptom Score (AdSS), a new end-point reflecting symptom severity and rescue medication use in allergic rhinoconjunctivitis trials. Methods To calculate the AdSS, the RTSS is adjusted as follows: if a patient takes rescue medication on day d, the day's AdSS (AdSS(d)) is defined as the value of RTSS(d) or AdSS(d-1), whichever is higher. The AdSS on the following day (AdSS(d+1)) is defined as the value of RTSS(d+1) or AdSS(d), whichever is higher. The average of the daily AdSSs (during the season) was calculated post hoc for two trials investigating the efficacy of five-grass pollen sublingual immunotherapy tablets in adult and paediatric patients and compared with the ARTSS and three other outcome measures (the average Rescue Medication Score (ARMS), the ARTSS and the average Combined Score). Results The average AdSS clearly discriminated between active and placebo treatments and confirmed the original ARTSS results. Adjustment for rescue medication use decreased the observed placebo effect. Conclusion and Clinical Relevance The average AdSS can be a valuable alternative to the ARTSS as a primary efficacy end-point in grass pollen allergic rhinoconjunctivitis trials. By adjusting the RTSS for rescue medication use, the AdSS can estimate symptom severity and the treatment effect more accurately. The AdSS is now being tested prospectively in large clinical trials.