Efficacy and Safety Evaluation of Sublingual Immunotherapy with Betula Pollen Extract in Patients with Moderate-to-Severe Birch Pollen-Induced Allergic Rhinitis

The primary objective of this Phase II-III study is to determine the most effective and best-tolerated dose of **SLI-RX-BET** in patients with moderate-to-severe allergic rhinitis or rhinoconjunctivitis due to birch pollen. This is assessed through the benefit-risk balance and the Combined Symptom and Medication Score (CSMS). Establishing the optimal dose is clinically relevant as it aims to improve patient outcomes by minimizing symptoms and medication use, thereby enhancing the quality of life for individuals affected by birch pollen allergy.

The clinical trial involves a total of **442 participants** who are both male and female, aged between 18 and 65 years. The study population consists of individuals diagnosed with moderate-to-severe **allergic rhinitis** or rhinoconjunctivitis due to birch pollen, as per the Allergic Rhinitis and its Impact on Asthma (ARIA) guideline. Participants may have well-controlled mild-to-moderate asthma, as defined by the Global Initiative for Asthma (GINA) guideline, or no asthma at all. The selection criteria required participants to have a forced expiratory volume in one second (FEV1) greater than 70% of the predicted normal value for those with asthma. Sensitization to Betula verrucosa pollen was confirmed through a positive skin prick test and serum allergen-specific IgE levels. Participants were also required to demonstrate compliance and the ability to use an electronic diary for self-evaluation of symptoms and medication use. The trial does not include a vulnerable population, and safety laboratory results for participants were within normal ranges or deemed not clinically significant.

The clinical trial is designed to evaluate the **efficacy** and safety of sublingual immunotherapy in patients with moderate-to-severe allergic rhinitis or rhinoconjunctivitis due to birch pollen. This is a Phase II-III, randomized, double-blind, placebo-controlled study. The trial aims to determine the most effective and best-tolerated dose of SLI-RX-BET, a sublingual spray solution containing **betula pollen extract**, by assessing the benefit-risk balance and the Combined Symptom and Medication Score (CSMS). The trial is expected to commence recruitment on August 15, 2025, and conclude by August 20, 2027.

Participants will be randomly assigned to receive either a low, mid, or high dose of SLI-RX-BET or a placebo, which is identical in appearance, smell, taste, and excipients but lacks the active substance. The study will involve multiple visits, starting with a screening visit to confirm eligibility based on criteria such as age, medical history, and sensitization to Betula verrucosa pollen. Participants must be between 18 and 65 years old, with a history of allergic rhinitis or rhinoconjunctivitis for at least two years, and must provide informed consent prior to any study-specific procedures.

Following the screening, participants will attend regular follow-up visits to monitor their response to treatment and any adverse effects. The primary endpoint is the absolute difference in mean CSMS during the Peak Birch Pollen Period (PBPP) between each active treatment group and the placebo group. Secondary endpoints include differences in symptom scores, quality of life assessments, and the safety profile of each dose. The trial will also evaluate the percentage of well and severe days, symptom-free days, and the response to a titrated Nasal Provocation Test (tNPT).

The expected duration of participant involvement is up to 301 days, with a maximum daily dose of 0.2 ml and a total dose not exceeding 60.2 ml. Conditions that may lead to early termination from the study include non-compliance with study procedures, significant adverse reactions, or withdrawal of consent. The study is not categorized as low intervention and is conducted under strict adherence to ethical guidelines and regulatory requirements.

The clinical trial involves the administration of several treatments to evaluate the efficacy and safety of sublingual immunotherapy in patients with birch pollen allergy. The experimental medications include three formulations of **SLI-RX-BET**, each containing **betula pollen extract** as the active substance. These formulations are administered as a sublingual spray solution. The **SLI-RX-BET LOW dose** is delivered in a maximum daily dose of 0.2 ml, with a total maximum dose of 60.2 ml over a treatment period of up to 301 days. The route of administration is sublingual, ensuring direct absorption through the mucous membranes under the tongue.

The **SLI-RX-BET MID dose** and **SLI-RX-BET HIGH dose** follow the same pharmaceutical form and administration route as the low dose. Both are also administered as sublingual spray solutions, with a maximum daily dose of 0.2 ml and a total maximum dose of 60.2 ml over the same treatment period of 301 days. The active substance, **betula pollen extract**, is a structurally diverse allergen, and the formulations are designed to assess the optimal dose for balancing efficacy and tolerability in the target patient population.

In addition to the experimental treatments, a **placebo preparation** is used as a comparator in the study. This placebo is formulated for sublingual use and is identical in appearance, smell, taste, and excipients to the active treatments, but it does not contain the active substance, i.e., the allergen extract. The placebo is administered in the same manner as the active treatments to ensure blinding and to serve as a control for evaluating the efficacy of the SLI-RX-BET formulations.

The efficacy of the sublingual immunotherapy in patients with birch pollen allergy will be assessed using the **Combined Symptom and Medication Score (CSMS)** as the primary endpoint. This endpoint is defined by the absolute differences in mean CSMS during the Peak Birch Pollen Period (PBPP) for each active treatment group compared to the placebo group. Secondary endpoints include absolute and relative differences in mean CSMS during the Birch Pollen Season (BPS), as well as differences in mean daily Symptom Scores (dSS) and daily Medication Scores (dMS) during both PBPP and BPS. Additionally, individual symptom scores for nasal and ocular symptoms, Global Rhinoconjunctivitis Discomfort measured with a 10.0-point Visual Analogue Scale (VAS), and changes in the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) will be evaluated.

Further assessments will include the percentage of well and severe days, defined by specific criteria related to symptom scores and medication use, and the percentage of symptom-free days during PBPP and BPS. The titrated Nasal Provocation Test (tNPT) will be used to evaluate the efficacy of each dose of SLI-RX-BET compared to placebo, focusing on the change in dosing steps required to provoke a positive response post-treatment. The safety and tolerability of each dose will also be analyzed by monitoring Treatment-Emergent Adverse Drug Reactions (TEADR) and the number of patients affected by TEADRs in each group.