Efficacy and Safety Evaluation of Sublingual Immunotherapy with Betula Pendula Pollen Extract in Patients with 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 **SULGEN® Spray Betula verrucosa** in patients with moderate-to-severe allergic rhinitis or rhinoconjunctivitis due to birch pollen. This is assessed by evaluating 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 **482 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/rhinoconjunctivitis** due to birch pollen, as per the Allergic Rhinitis and its Impact on Asthma (ARIA) guideline, for a minimum duration of two years. Participants were selected based on their ability to comply with study requirements, including the use of an electronic diary for self-evaluation of symptoms and medication. The trial excludes vulnerable populations and focuses on individuals with well-controlled mild-to-moderate or no asthma, as defined by the Global Initiative for Asthma (GINA) guideline. Participants are required to have a forced expiratory volume (FEV1) in one second greater than 70% of the predicted normal value if they have asthma. Sensitization to Betula verrucosa pollen is confirmed through a positive skin prick test, serum allergen-specific IgE levels, and a positive response to nasal provocation. Safety laboratory results must be 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 well-tolerated dose of SULGEN® Spray Betula verrucosa, focusing on the benefit-risk balance and the Combined Symptom and Medication Score (CSMS). The trial is expected to run from August 2023 to August 2025, with participant involvement lasting up to 301 days.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, medical history, and sensitization to Betula verrucosa pollen. Following successful screening, participants will be randomized into treatment groups. The trial includes multiple follow-up visits to monitor efficacy and safety, with assessments such as the titrated Nasal Provocation Test (tNPT) and evaluations of the CSMS during the Peak Birch Pollen Period (PBPP) and Birch Pollen Season (BPS). The end-of-study visit will conclude the trial, where final assessments and data collection will occur.

Participants are expected to adhere to the study protocol, including the completion of an electronic diary for self-evaluation of symptoms and rescue medication use. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or withdrawal of consent. The primary endpoint is the absolute difference in mean CSMS during the PBPP between active and placebo groups. Secondary endpoints include differences in symptom scores, quality of life assessments, and safety evaluations through Treatment-Emergent Adverse Drug Reactions (TEADR).

The clinical trial involves the use of several experimental and non-experimental treatments. The **Provokationstest Birkenpollen LETI** is an experimental medication formulated as a **solution for provocation test**. It contains **Betula alba pollen extract** as the active substance. The pharmaceutical form is a powder, solvent, and diluent for the preparation of a provocation test solution, administered via **nasal spray**. The maximum daily dose is 1 ml, with a total dose of 1.6 ml over a treatment period of 2 days.

The **SULGEN® Spray Betula verrucosa** is another experimental treatment available in low, mid, and high doses. It is a **sublingual spray, solution** containing **Betula pendula pollen extract**. The maximum daily dose is 0.2 ml, with a total dose of 60.2 ml over a treatment period of 301 days. The administration route is **sublingual use**.

Non-experimental treatments include the **ALK-prick Positiv-Kontrolle**, a **solution for skin-prick test** containing **histamine dihydrochloride**. It is administered topically with a maximum daily dose of 1 drop, and the treatment period is 1 day. Similarly, the **MometaHEXAL Nasenspray** is a **nasal spray, suspension** containing **mometasone furoate**, with a maximum daily dose of 0.1 mg and a total dose of 33.4 mg over 11 days.

Additional non-experimental treatments include various **solutions for skin-prick tests** containing allergens such as **Dermatophagoides pteronyssinus**, **Artemisia vulgaris**, and **Phleum pratense**. These are administered topically with a maximum daily dose of 1 drop and a treatment period of 1 day. The **Lorano akut** and **Prednisolon JENAPHARM®** are oral tablets containing **loratadine** and **prednisolone**, respectively, with maximum daily doses of 10 mg and 40 mg over 11 days.

A **sublingual placebo preparation** is also used, matching the appearance, smell, taste, and excipients of the active treatment but lacking the active allergen extract. This placebo is used to ensure blinding in the trial.

The efficacy of the clinical trial will be assessed using the primary endpoint, which is defined as the absolute differences in mean **CSMS** (Combined Symptom and Medication Score) during the Peak Birch Pollen Period (PBPP) of each active treatment group compared to the placebo treatment group. Secondary endpoints include absolute and relative differences in mean CSMS during the Birch Pollen Season (BPS) between active and placebo treatment groups, as well as differences in mean daily Symptom Score (dSS) and daily Medication Score (dMS) during PBPP and BPS. Additional assessments will involve the Global Rhinoconjunctivitis Discomfort using a Visual Analogue Scale (VAS), changes in the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores, and the percentage of well and severe days during PBPP and BPS. Symptom-free days will also be evaluated as days without symptoms and without the need for rescue medication.

The efficacy of each dose of SULGEN® Spray Betula verrucosa will be further assessed through the titrated Nasal Provocation Test (tNPT), which measures the percentage of patients with an increased dosing step and the change in the number of dosing steps needed to provoke a positive response post-treatment compared with pre-treatment. The trial will also analyze the safety and tolerability of each dose compared to placebo by monitoring Treatment-Emergent Adverse Drug Reactions (TEADR) and the number of patients affected by TEADRs in each group.