In this responder analysis, we revealed the superior efficacy of rupatadine over placebo at improving SAR symptoms. We also evidenced that rupatadine response was dose-dependent, achieving faster and higher improvements with 20 mg over the whole follow-up period.
Strengths and weaknesses
The main strength of this study is the comprehensive analysis performed, including data on symptom response evolution, responder proportions, and time to achieve response. To the best of our knowledge, no previous study on SAR has addressed all these analyses before, including several multicentre, double-blind RCTs with patients with moderate-severe SAR. In addition, this study analysed data from 1470 patients, representing a considerable sample size. Baseline characteristics in our study were similar to those of previous studies, reinforcing the validity of our results [
23‐
26,
29,
30]. The main limitations of the study are the post hoc analysis and duration of the study (2 weeks), which does not allow capturing the complete stabilization of clinical symptoms. The lack of safety analyses is an additional limitation of the study. In this regard, rupatadine was safe and well-tolerated in several randomized clinical trials [
17,
23,
24,
26,
31], showing a similar safety profile compared with other antihistamines such as desloratadine, loratadine, cetirizine, and ebastine [
17]. Furthermore, this analysis did not include patients with mild AR who frequently self-medicate and are rarely seen by specialists. In contrast, it included patients with moderate-to-severe AR who represent the patient population treated in allergology, ear, nose and throat (ENT) or respiratory units. Additionally, the clinical relevance of these results should be interpreted considering the potential influence of patient-related factors like disease severity, presence of comorbidities or the major severity of nasal or ocular symptoms.
Discussion of results
Upon treatment with rupatadine, symptom scores (T4NSS, T2OSS, and T6SS) gradually decreased from baseline over the 14-day treatment period, with higher improvements in the 20 mg group compared to the 10 mg group. The proportion of responders was systematically higher in rupatadine groups than in the placebo group for all the symptom scores across the two response cut-offs (≥ 50% and ≥ 75%). The time to achieve the 50% and 75% response was shorter in the rupatadine 20 mg than in the rupatadine 10 mg group and placebo groups for all the symptom scores. The proportion of patients with a complete/near-to-complete response for T4NSS and T6SS was statistically higher in rupatadine groups than in the placebo group.
One of the most important findings of this study is that, for all the analyses performed, rupatadine 20 mg provided better responses than rupatadine 10 mg or placebo, as shown by the higher reduction of symptoms and proportion of responders, and the faster onset of action. In the systematic review performed by Compalati et al., the comparison between rupatadine 10 mg and 20 mg showed no statistically significant advantage, but rupatadine 20 mg compared favourably [
20].
The analysis of daily symptom scores showed that rupatadine provided both early and sustained responses, as previously described [
19]. The evolution of symptom scores in patients treated with rupatadine was characterized by a rapid symptom relief followed by a gradual improvement for the following 14 days. This fast onset of action agrees with the results from pharmacokinetic and nasal challenge studies previously showing the rapid absorption of rupatadine [
22,
32,
33]. In our study, the initial decrease was more abrupt from day 1 to 5, followed by more stable effects thereafter. Since nasal (T4NSS) and global (T6SS) symptoms still decreased from day 11 to 14, it would be interesting to assess rupatadine response for longer time periods to obtain the time to achieve maximal reductions. In this regard, the study of Lukat et al. confirmed the efficacy of rupatadine 10 mg after 4 weeks of treatment, with a 46% reduction of baseline symptoms [
23].
In AR, establishing minimally clinical important differences that translate into clinical improvement remains controversial and has been scarcely addressed [
34]. Regulatory authorities suggest measuring response to treatment using a responder analysis to demonstrate the magnitude of the clinical effect. The EMA guideline on the treatment of allergic rhinoconjunctivitis recommends the analysis in terms of responders (≥ 50% reduction) to assess the clinical relevance of treatments [
27], which has been recently used in AR studies [
28]. Following the EMA guideline, we found a high proportion of responders for both response cut-offs (≥ 50% and ≥ 75%), with higher rates observed at 20 mg. Remarkably, after 2 weeks of treatment with rupatadine 20 mg, a proportion of responders greater than 50% for the stringent cut-off of 75% response was observed for all the symptom scores. The high percentage of patients with a dramatic reduction in symptoms reinforces the clinical benefit of this antihistaminic treatment and can have significant consequences in clinical practice.
The EMA guideline also states that efficacy assessments should separately prove the improvement in nasal and ocular symptoms [
27]. The number of patients who achieved a complete/near-to-complete response for both symptom scores was higher in rupatadine groups than in the placebo group, with higher proportions in the 20 mg group. Concretely, around 54% of patients treated with rupatadine reached both complete/near-to-complete responses after 7 days of treatment and approximately 65% (T4NSS) and 67% (T6SS) did so after 14 days of treatment.
One of the distinctive analyses of the present study is the assessment of the time to achieve a percentage of responders. Rupatadine 20 mg achieved faster a proportion of responders than rupatadine 10 mg or placebo for all symptom scores. This analysis is of great value to consider when selecting treatment dosage in patients with SAR, showing that doubling the dose of rupatadine significantly shortens the time to achieve a clinically meaningful effect (a reduction of 4.4 and 5.5 days in T4NSS for ≥ 50% and 75% responses, respectively). Rupatadine is authorized at 10 mg in most of the countries for adults and adolescents (over 12 years of age), whereas both 10 mg and 20 mg doses were recently authorized in Japan. Although 20 mg rupatadine was well-tolerated in Caucasian and Japanese patients, an increase in somnolence was observed in some patients with AR with this higher dose. Therefore, previous studies point out to a better balance between efficacy and safety at 10 mg, and justify the use of higher doses only for patients with severe symptoms [
24].
We observed a differential trend between nasal and ocular symptoms. Differences between rupatadine groups in symptom reduction were not statistically significant for the T2OSS at any time point, and this symptom score clearly showed narrower time intervals to achieve a prespecified percentage of responders between rupatadine groups. These results could indicate that the resolution of ocular symptom is less dependent on rupatadine dose, which could be attributed to the oral route of administration that exerts a faster onset of action and better control on nasal symptoms [
35]. However, these results should be analysed cautiously considering that the T2OSS only comprises two symptoms (eye itching and tearing) with a lesser contribution to the total score compared to the four nasal symptoms. In any case, the improvement of rupatadine on both nasal and ocular symptoms was clearly proven in the present pooled analysis.
This post hoc analysis may help physicians better assess patients’ phenotypes for treatment. Future work should comprise studies comparing several anti-H1 compounds according to the described criteria and correlating whether the cut-off responses defined in this study translate into quality of life improvements.