Tree Pollen Tablet Cuts Allergy Symptoms in Canadian Children, Phase III Subgroup Shows

Canadian children and adolescents with tree pollen allergy experienced fewer symptoms and used less symptom-relieving medication when treated with a sublingual immunotherapy tablet dissolved under the tongue, according to a post hoc analysis of a large phase III trial published in Allergy, Asthma & Clinical Immunology. The analysis, led by Rémi Gagnon and colleagues, isolated the 87 Canadian participants from a randomized, double-blind, placebo-controlled trial that enrolled 952 children across Europe, Canada, and Russia, and found that the tablet reduced the average total combined score of symptoms and medication use by 26.8 percent compared with placebo during the birch pollen season, by 32.0 percent across the broader tree pollen season, and by 46.6 percent during the oak pollen season. The largest effect appeared during days of oak season that did not overlap with birch, alder, or hazel pollen seasons, where the reduction reached 50.6 percent.

The trial, registered as EudraCT 2020-004372-17 and NCT04878354, randomized participants aged 5 to 17 years with moderate-to-severe tree pollen allergic rhinitis and/or conjunctivitis to receive either a daily tree sublingual immunotherapy tablet or a placebo. The tablet contained a standardized allergen extract from birch pollen at a 12 SQ-Bet dose, manufactured by ALK-Abello of Hørsholm, Denmark. Treatment began at least 12 weeks before the anticipated tree pollen season and continued through it, for a total duration of up to 52 weeks. The first dose was administered under clinical observation at the study site, after which participants or their caregivers dosed at home. Participants had free access to symptom-relieving medication throughout the tree pollen season, and the analysis counted both symptoms and medication use together so that relief achieved through drugs could not mask the underlying disease burden.

The primary endpoint was the average total combined score during the birch pollen season, defined as the sum of the rhinoconjunctivitis daily symptom score and the daily medication score. Symptoms of runny nose, blocked nose, sneezing, itchy nose, gritty or red and itchy eyes, and watery eyes were scored from 0 to 3 for severity, giving a maximum daily symptom score of 18. Use of oral antihistamines, ocular antihistamines, and intranasal corticosteroids was scored on a scale reaching a maximum of 20, so the maximum total combined score was 38. Participants or caregivers recorded these values daily in an electronic diary during the tree pollen season. Key secondary endpoints included the average total combined score across the whole tree pollen season, which comprised the birch, alder, hazel, and oak pollen seasons, as well as separate symptom and medication scores during each period.

Pollen seasons were defined objectively from measurements taken at two stations in Quebec and Montreal. The birch pollen season began on the first day of three consecutive days with a birch pollen count of at least 30 grains per cubic meter and ended after the last such occurrence, while the hazel, alder, and oak seasons used a threshold of at least 10 grains per cubic meter. The tree pollen season included all days falling within any of these four seasons, whether or not they formed a continuous period. Pure oak pollen season was defined as the days of oak season with no overlap from the birch, alder, or hazel seasons. Birch pollen counts averaged 240 grains per cubic meter in the 2023 season and 195 in 2022, while oak counts averaged 244 and 90 respectively, and the 2022 birch and oak seasons lasted only 7 and 14 days compared with roughly a month for birch and alder and 19 days for oak in 2023.

Statistically, the Canadian subgroup results carried an important caveat: the absolute difference in the total combined score during the birch pollen season was 1.89 points, with a 95 percent confidence interval spanning from minus 0.71 to 4.49 and a p value of 0.138, meaning this primary endpoint did not reach statistical significance in the subgroup. The tree pollen season difference of 2.14 points was significant at p equal to 0.042, the oak pollen season difference of 3.70 points at p equal to 0.004, and the pure oak season difference of 4.20 points at p equal to 0.005. By contrast, in the full trial population of 952 participants, the tablet reduced the average total combined score by 19.2 percent during the birch season with an absolute difference of 1.13 points and a p value of 0.002, by 16.8 percent during the tree season, by 23.4 percent during the oak season, and by 19.9 percent during the pure oak season, all statistically significant.

The analysis used a treatment policy estimand, a conservative statistical approach recommended by the International Council for Harmonization that includes all collected data, even from participants who discontinued treatment, to reflect effectiveness under real-world conditions. Missing values due to lack of efficacy or treatment-related adverse events were imputed from the placebo group, while missing values from other causes were imputed from the participant’s own treatment group. Imputation was performed within age strata using unrestricted random sampling with replacement, generating 1000 multiple imputed datasets. Each dataset was analyzed with a linear mixed effects model that included treatment, age group, and cohort as fixed factors and pollen station within cohort as a random effect, with different residual errors for each treatment group and denominator degrees of freedom calculated by Kenward and Roger’s approximation. Results were combined across datasets using Rubin’s rule, back-transformed from the square root scale, and confidence intervals for relative differences were derived with Fieller’s theorem.

Within the Canadian subgroup, the treatment effect was consistent across age bands. Among children aged 5 to 11 years, the absolute difference in the birch season total combined score corresponded to a 24.0 percent reduction versus placebo, and among adolescents aged 12 to 17 years it corresponded to a 27.5 percent reduction. Reductions in the daily symptom score and the daily medication score were also observed during both the birch and tree pollen seasons. The authors noted that the relative difference of 26.8 percent during the birch season exceeded the 20 percent clinically relevant threshold proposed by the World Allergy Organization, and that the absolute difference of 1.89 met the minimal clinically important difference of at least 1 point that the primary trial was designed to demonstrate, a margin they described as corresponding to a one-severity-class improvement in a single symptom every day of the season or to roughly five fewer days of antihistamine use per month.

Safety findings supported tolerability. In the Canadian subgroup there were no treatment-related serious adverse events, no events requiring epinephrine administration, no systemic allergic reactions, no severe local swellings or mouth or throat edema, no severe asthma exacerbations, and no events of eosinophilic esophagitis. A numerically higher proportion of participants in the active group reported oral allergy syndrome compared with placebo, 11 percent versus none, and the authors observed that this rate was higher than in the total trial population, where it was below 2 percent, and higher than in adults, where it was below 5 percent. Two of the five affected participants had existing oral allergy syndrome before the trial but reported it as an adverse event during the study, and the authors suggested that regional reporting differences may reflect heightened emphasis on oral allergy syndrome among Canadian investigators. Discontinuation due to adverse events was low and similar between groups, at 4 percent with the tablet and 5 percent with placebo.

The Canadian subgroup differed from the full trial in ways that may explain the larger apparent effect sizes. The mean age was 10.8 years, 96.6 percent of participants were White, twice as many males as females were enrolled in the active group, 83.9 percent were polysensitized, and 26.4 percent had asthma. The authors cautioned that the magnitudes of the absolute and relative differences were greater in the Canadian subgroup than in the full population for all measured seasons, and that this may simply be an artifact of the smaller sample size, since analyses of multiple phase III trials of sublingual immunotherapy tablets have shown consistent treatment effects across geographic regions. They also raised the alternative possibility that a pronounced priming effect from early alder exposure and high birch pollen counts in the second cohort may have amplified the treatment effect observed during the later oak season.

The authors framed the findings as the first evidence of efficacy and safety for the tree sublingual immunotherapy tablet specifically in Canadian children and adolescents, noting that the pivotal adult phase III trial did not include North American sites, although a Canadian phase II environmental exposure chamber trial in adults had shown a 25 percent reduction in total symptom score during birch exposure and 24 percent during oak exposure after 24 weeks. Because oak trees grow throughout much of southern Canada and birch sensitivity affects roughly 25 to 35 percent of atopic individuals depending on region, the significant effect during the oak season carries particular local relevance. The authors concluded that the consistent efficacy and favorable safety profile support the tablet’s inclusion as a therapeutic option in Canadian clinical practice, while emphasizing that the small subgroup size of 87 participants means the results should be interpreted with caution, and that caregiver-completed symptom scoring for younger children adds a layer of subjectivity to the outcome measures.

Subject of Research: Efficacy and safety of a tree pollen sublingual immunotherapy tablet in Canadian children with allergic rhinitis and/or conjunctivitis

Article Title: Efficacy and safety of the tree sublingual immunotherapy tablet in the subpopulation of Canadian children with allergic rhinitis and/or conjunctivitis: phase III trial results

Article References: Gagnon, R., Dalgaard, T., Ortving, G. S., Gappa, M., & Nolte, H. (2026). Efficacy and safety of the tree sublingual immunotherapy tablet in the subpopulation of Canadian children with allergic rhinitis and/or conjunctivitis: phase III trial results. Allergy, Asthma & Clinical Immunology, 22(1), Article 55. https://doi.org/10.1186/s13223-026-01054-w

Image Credits: AI Generated

DOI: 10.1186/s13223-026-01054-w

Keywords: allergic rhinitis, conjunctivitis, sublingual immunotherapy, birch pollen, oak pollen, pediatric allergy, phase III trial, Canada, placebo-controlled, allergy immunotherapy, total combined score, post hoc analysis