The Allergic Rhinitis - Clinical Investigator Collaborative (AR-CIC): nasal allergen challenge protocol optimization for studying AR pathophysiology and evaluating novel therapies

Abstract

Background: The Nasal Allergen Challenge (NAC) model allows the study of Allergic Rhinitis (AR) pathophysiology and the proof of concept of novel therapies. The Allergic Rhinitis - Clinical Investigator Collaborative (AR-CIC) aims to optimize the protocol, ensuring reliability and repeatability of symptoms to better evaluate the therapies under investigation.

Methods: 20 AR participants were challenged, with 4-fold increments of their respective allergens every 15 minutes, to determine the qualifying allergen concentration (QAC) at which the Total Nasal Symptom Score (TNSS) of ≥10/12 OR a Peak Nasal Inspiratory Flow (PNIF) reduction of ≥50% from baseline was achieved. At the NAC visit, the QAC was used in a single challenge and TNSS and PNIF were recorded at baseline, 15 minutes, 30 minutes, 1 hour, and hourly up to 12 hours. 10 additional ragweed allergic participants were qualified at TNSS of ≥8/12 AND ≥50% PNIF reduction; the Cumulative Allergen Challenge (CAC) of all incremental doses was used during the NAC visit. 4 non-allergic participants were challenged with the highest allergen concentration.

Results: In the QAC study, a group qualified by only meeting PNIF criteria achieved lower TNSS than those achieving either TNSS criteria or PNIIF+TNSS (p<0.01). During the NAC visit, participants in both studies reached their peak symptoms at 15minutes followed by a gradual decline, significantly different from non-allergic participants. The "PNIF only" group experienced significantly lower TNSS than the other groups during NAC visit. QAC and CAC participants did not reach the same peak TNSS during NAC that was achieved at screening. QAC participants qualifying based on TNSS or TNSS+PNIF managed to maintain PNIF scores.

Conclusions: Participants experienced reliable symptoms of AR in both studies, using both TNSS and PNIF reduction as part of the qualifying criteria proved better for qualifying participants at screening. Phenotyping based on pattern of symptoms experienced is possible and allows the study of AR pathophysiology and can be applied in evaluation of efficacy of a novel medication. The AR-CIC aims to continue to improve the model and employ it in phase 2 and 3 clinical trials.

Keywords: Allergic rhinitis; Clinical investigator collaborative; Nasal allergen challenge.

Figure 1

Analysis of QAC study. A - B show the mean and standard errors of TNSS and PNIF recorded by each group at each time point during the NAC visit (significance between time points: p<0.0001). The “PNIF only” group experienced consistently low TNSS over all time points (compared to “TNSS only” group: p<0.01 at 15 minutes and 1 hour, p<0.001 at 30 minutes; compared to “TNSS +PNIF” group: p<0.05 at 15 minutes) while the “TNSS only” group had the lowest PNIF recordings throughout the study. The “TNSS+PNIF” group had comparable TNSS to the “TNSS only” group and comparable PNIF to the “PNIF only” group. C - D. All 3 groups experienced a decline in TNSS from screening to NAC visit, but not all are statistically significant. “TNSS+PNIF” group had a significant (p<0.05) decline in NAC TNSS compared to screening. However, “TNSS only” and “TNSS+PNIF” groups both had a non-significant increase in PNIF during the NAC from screening while the “PNIF only” group experienced a decline (p<0.05).

Figure 2

Comparing QAC (Queen’s University only) and CAC studies. A and B. Mean TNSS and PNIF scores including non-allergic participants. Allergic participants experienced the highest scores at 15 minutes (QAC TNSS: 15 minutes vs 4 and 5 hour time point p<0.05, vs 6^th hour to 12^th hour p<0.001) (CAC TNSS: 15 minutes vs 2 hour p<0.05, vs 3 to 12^th hour p<0.001) compared to non-allergic participants who did not experience change from baseline. Most time points were significantly greater than baseline scores (QAC: Baseline TNSS vs 15 minutes to 3 hours p< 0.001 and p<0.01 at the 4^th and 5^th hours) (CAC: Baseline TNSS vs 15 minutes to 2 hours p<0.001, vs 3^rd hour p<0.01, vs 4^th hour p<0.05). PNIF scores followed a similar pattern (QAC PNIF: Baseline vs 15 and 30 minutes p<0.001, vs 1 hour p<0.01; while 15 minutes time point vs 3 hours to the 12^th hour p<0.001) (CAC PNIF: Baseline time point vs 15 minutes up to 1 hour p<0.001 and vs 2 hours p<0.05; while the 15 minute time point vs 3 hours p<0.05, vs 5^th to the 7^th hour p<0.01, 8^th hour p<0.001, 9^th to the 11^th hour p<0.01, and 12^th hour p<0.001). While there were significant differences between the time points for allergic participants (two way ANOVA p<0.0001 for both TNSS and PNIF in both studies), there were no such significance experienced by non-allergic participants. C - D: Strong correlation between TNSS and PNIF exists in both studies, although the correlation is stronger in the CAC study (Person’s correlation QAC: R²=0.8981 p<0.0001, CAC: R²=9576 p<0.0001).

Figure 3

Participants divided based on the phases of AR experienced based on TNSS. Participants in the QAC (Figure 3 A) and CAC (Figure 3 B) studies who had an Early Phase Responders (EPR) and Dual Phase Responders (DPR) experienced a peak at 15 min. following NAC while those that experienced a protracted EPR (pEPR) had a gradual rise in TNSS up to 1 hr. This suggests that the 1hr time point ensures that the maximal amount of cytokines are secreted by this time point in all participants and therefore is the best time point for sampling nasal cytokines. While EPR experienced a drop in TNSS following the peak, pEPR maintained their symptoms level before declining, DPR experienced a drop in TNSS following the peak but did rise again later in the study. Statistical analysis was not possible since participant populations experiencing certain phases were too small to compare. Nevertheless, differences in scores over the 12 hour period were distinct from one participant population to the other.