Efficacy and Safety Evaluation of Subcutaneous Cluster-Immunotherapy with Allergen Extract from Phleum pratense Pollen in Moderate-to-Severe Grass Pollen Allergy

The primary objective of this Phase II-III study is to determine the most effective and best-tolerated dose of **CLU-RX-PHL** in patients with moderate-to-severe allergic rhinitis/rhinoconjunctivitis due to grass 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 grass pollen allergy.

The clinical trial involves a total of **530 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 grass 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 80% of the predicted normal value for asthmatic patients. Sensitization to Phleum pratense 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. 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 subcutaneous cluster-immunotherapy 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 aims to determine the most effective and best-tolerated dose of CLU-RX-PHL, a **solution for injection** containing an **allergen extract from Phleum pratense pollen, glutaraldehyde-modified**. The study will compare three different doses of CLU-RX-PHL (high, medium, and low) against a placebo. The trial is expected to commence on October 15, 2025, and conclude by December 10, 2027.

Participants will be involved in the study for a maximum treatment period of 50 weeks. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to be between 18 and 65 years old, with a history of grass pollen allergy for at least two years, and to have signed an informed consent form. Participants must also demonstrate compliance with study procedures, including the use of an electronic diary for symptom tracking.

Study visits will be structured as follows: the inclusion visit will involve screening procedures such as a skin prick test and serum IgE measurement to confirm sensitization to Phleum pratense pollen. Follow-up visits will occur at regular intervals to assess the primary endpoint, which is the absolute difference in mean Combined Symptom and Medication Score (CSMS) during the Peak Grass Pollen Period (PGPP) between active and placebo groups. Secondary endpoints include differences in symptom scores and quality of life measures. The end-of-study visit will involve a final assessment of these endpoints and any adverse events.

Participants may be withdrawn from the study if they experience significant adverse reactions, fail to comply with study procedures, or if the investigator deems it necessary for safety reasons. The trial's rigorous design ensures that data collected will provide valuable insights into the optimal dosing and safety profile of CLU-RX-PHL for treating grass pollen-induced allergic conditions.

The clinical trial involves the administration of **CLU-RX-PHL high dose**, a **solution for injection** containing an **allergen extract from Phleum pratense pollen, glutaraldehyde-modified**. This experimental medication is administered via **subcutaneous use**. The maximum daily dose is 0.7 ml, with a total maximum dose of 5.7 ml over a treatment period of 50 days. The medication is not formulated for pediatric use and is produced by ROXALL MEDIZIN GMBH. The active substance is classified under the ATC code V01AA02, indicating its use in grass pollen allergies.

Another experimental treatment in the trial is **CLU-RX-PHL medium dose**, which also consists of a **solution for injection** with the same active substance, **allergen extract from Phleum pratense pollen, glutaraldehyde-modified**. The administration route is **subcutaneous use**, with a maximum daily dose of 0.7 ml and a total maximum dose of 5.7 ml over 50 days. This formulation is similarly not intended for pediatric use and is manufactured by ROXALL MEDIZIN GMBH.

The trial also includes **CLU-RX-PHL low dose**, a **solution for injection** containing the same active substance, **allergen extract from Phleum pratense pollen, glutaraldehyde-modified**. It is administered via **subcutaneous use**. The dosing schedule allows for a maximum daily dose of 0.7 ml and a total maximum dose of 5.7 ml over a 50-day period. This formulation is not designed for pediatric patients and is produced by ROXALL MEDIZIN GMBH.

A **placebo preparation** is utilized in the study, designed for **subcutaneous use**. It is formulated to have the same appearance, smell, taste, and excipients as the active treatments but does not contain the active substance, i.e., the allergen extract. This placebo serves as a comparator to evaluate the efficacy and safety of the experimental treatments.

The efficacy of the clinical trial will be assessed using the **Combined Symptom and Medication Score (CSMS)** as the primary endpoint. This endpoint will measure 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 will include absolute and relative differences in mean CSMS during the Grass Pollen Season (GPS), as well as differences in mean daily Symptom Scores (dSS) and daily Medication Scores (dMS) during both PGPP and GPS. Additionally, individual symptom scores for nasal and ocular symptoms will be evaluated.

Further assessments will involve changes in Global Rhinoconjunctivitis Discomfort using a 10.0-point Visual Analogue Scale (VAS) and the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores, comparing baseline and post-treatment results between active and placebo groups. The trial will also calculate the percentages of well and severe days, defined by specific criteria related to symptom scores and medication use, during PGPP and GPS. Symptom-free days will be identified as days without symptoms and without the need for rescue medication.

The efficacy of each dose of CLU-RX-PHL will also be evaluated through a titrated Nasal Provocation Test (tNPT). This test will determine the percentage of patients with an increased dosing step and the change in the number of dosing steps required to provoke a positive response post-treatment compared to pre-treatment. The analysis will focus on the change in response to nasal provocation from baseline to the end of treatment across the four treatment groups.