Efficacy and Safety Evaluation of Phleum Pratense Pollen Extract Sublingual Immunotherapy in Moderate-to-Severe Grass Pollen-Induced Allergic Rhinitis Patients

The primary objective of this Phase II-III study is to establish the **efficacy** and **safety** of sublingual immunotherapy (SLI-RX-PHL) in patients with moderate-to-severe allergic rhinitis or rhinoconjunctivitis due to grass pollen. The study aims to evaluate the treatment's impact on the Combined Symptom and Medication Score (CSMS) and assess the benefit-risk balance across different doses. This is clinically relevant as it addresses the need for effective management of allergic rhinitis, which significantly impacts patients' quality of life and can lead to complications such as asthma.

The clinical trial involved a total of **442 participants** diagnosed with moderate-to-severe **allergic rhinitis** or rhinoconjunctivitis due to grass pollen, as per the Allergic Rhinitis and its Impact on Asthma (ARIA) guideline. The study population comprised both male and female patients aged between 18 and 65 years. Participants were selected based on their medical history of allergic rhinitis for at least two years, with or without well-controlled mild-to-moderate asthma, as defined by the Global Initiative for Asthma (GINA) guideline. The trial did not include a vulnerable population. Participants were required to demonstrate sensitization to Phleum pratense pollen through a positive skin prick test and serum allergen-specific IgE levels. Additionally, they needed to have a Forced Expiratory Volume (FEV1) in one second greater than 70% of the predicted normal value if asthmatic. Lifestyle considerations such as diet and physical activity were not specified. The trial ensured that participants could comply with study requirements, including the use of an electronic diary for symptom and medication tracking. Safety laboratory results were required to be within normal ranges or deemed not clinically significant.

The clinical trial is designed to evaluate the **efficacy** and safety of sublingual immunotherapy using SLI-RX-PHL in patients with moderate-to-severe allergic rhinitis or rhinoconjunctivitis due to grass pollen. This is a Phase II-III, randomized, double-blind, placebo-controlled study. The trial will involve multiple treatment groups receiving different doses of SLI-RX-PHL, including high, medium, and low doses, as well as a placebo group. The active substance in the treatment is **Phleum pratense pollen extract**, administered as a sublingual spray solution. The trial is expected to commence recruitment on October 1, 2025, and conclude by November 24, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, medical history, and sensitization to grass pollen. Following successful screening, participants will be randomized into one of the treatment groups. The trial will include regular follow-up visits to monitor safety, adherence, and response to treatment, with assessments of the Combined Symptom and Medication Score (CSMS) as a primary endpoint. Secondary endpoints will evaluate differences in symptom scores, quality of life, and safety profiles between active and placebo groups. The end-of-study visit will involve a final assessment of the treatment's impact and any adverse events.

The expected duration of participant involvement is up to 50 weeks, with a maximum total dose of 70 ml of the investigational product. Conditions that may lead to early termination from the study include non-compliance with study procedures, withdrawal of consent, or the occurrence of significant adverse events. The trial aims to provide comprehensive data on the benefit-risk balance of SLI-RX-PHL, contributing to the understanding of its potential as a treatment for grass pollen-induced allergic conditions.

The clinical trial involves the administration of three experimental medications, each containing **Phleum pratense pollen extract** as the active substance. The medications are formulated as sublingual spray solutions and are produced by ROXALL MEDIZIN GMBH. The first experimental medication, SLI-RX-PHL high dose, is administered via sublingual use. The maximum daily dose is 0.2 ml, with a total maximum dose of 70 ml over a treatment period of 50 days. The active substance is classified as a structurally diverse substance - allergen, specifically targeting grass pollen allergies.

The second experimental medication, SLI-RX-PHL medium dose, also contains **Phleum pratense pollen extract** and is administered in the same pharmaceutical form and route as the high dose. The dosing schedule is identical, with a maximum daily dose of 0.2 ml and a total maximum dose of 70 ml over 50 days. This formulation is designed to assess the efficacy and safety at a medium dosage level.

The third experimental medication, SLI-RX-PHL low dose, follows the same administration and dosing parameters as the high and medium doses. It is intended to evaluate the therapeutic effects and safety profile at a lower dosage of **Phleum pratense pollen extract**. The sublingual spray solution is administered with a maximum daily dose of 0.2 ml and a total maximum dose of 70 ml over the course of 50 days.

A placebo preparation is also utilized in the study, which is identical in appearance to the experimental medications but does not contain the active substance, i.e., the allergen extract. The placebo is used to provide a comparator for evaluating the efficacy and safety of the active treatments. The placebo is administered in the same manner as the active treatments to ensure blinding and consistency in the trial.

The efficacy of the sublingual immunotherapy (SLI-RX-PHL) in patients with grass pollen allergy will be assessed using the **Combined Symptom and Medication Score (CSMS)** as the primary endpoint. The primary efficacy endpoint is defined as the absolute differences in mean CSMS during the Peak Grass Pollen Period (PGPP) for each active treatment group compared to the placebo group. Secondary endpoints include absolute and relative differences in mean CSMS during the Grass Pollen Season (GPS) between active and placebo groups, as well as differences in mean daily Symptom Scores (dSS) and daily Medication Scores (dMS) during PGPP and GPS.

Additional secondary endpoints involve changes in Global Rhinoconjunctivitis Discomfort using a 10.0-point Visual Analogue Scale (VAS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores, comparing pre- and post-treatment results between active and placebo groups. The study will also evaluate the percentage of well and severe days, symptom-free days, and the efficacy of each dose of SLI-RX-PHL through a titrated Nasal Provocation Test (tNPT). The tNPT will assess the percentage of patients with an increased dosing step and changes in the number of dosing steps needed to provoke a positive response post-treatment compared to pre-treatment.