Efficacy and Safety Evaluation of Subcutaneous Cluster-Immunotherapy with Birch Pollen Allergoid Glutaraldehyde Modified in Moderate-to-Severe Allergic Rhinitis

The primary objective of this Phase II-III study is to determine the most effective and best-tolerated dose of **CLU-RX-BET** in patients with moderate-to-severe allergic rhinitis or rhinoconjunctivitis due to birch pollen. The evaluation focuses on the benefit-risk balance and the Combined Symptom and Medication Score (CSMS). This is clinically relevant as it aims to optimize treatment efficacy while minimizing adverse effects, thereby improving patient outcomes in managing birch pollen allergy.

The clinical trial involves a total of **660 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 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 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 were required to be within normal ranges or not clinically significant. Lifestyle factors such as diet and physical activity were not specified as part of the selection criteria.

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 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 CLU-RX-BET, a solution for injection containing **birch pollen allergoid glutaraldehyde modified**, by assessing the benefit-risk balance and the Combined Symptom and Medication Score (CSMS). The study is expected to commence recruitment on July 1, 2025, and conclude by August 15, 2027.

Participants will be randomly assigned to one of four groups: three active treatment groups receiving low, mid, or high doses of CLU-RX-BET, and a placebo group receiving a preparation identical in appearance, smell, taste, and excipients but without the active substance. The trial will involve multiple study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, medical history, and sensitization to Betula verrucosa pollen. Participants will be required to have a positive skin prick test and serum allergen-specific IgE levels, among other criteria.

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 and tolerability of the treatment. The trial will also evaluate the efficacy of each dose using a titrated Nasal Provocation Test (tNPT).

The expected duration of participant involvement is up to 50 weeks, with conditions for early termination including non-compliance with study procedures, withdrawal of consent, or adverse events deemed significant by the study investigators. Participants will complete an electronic diary for self-evaluation of symptoms and rescue medication use throughout the study. The end-of-study visit will involve a final assessment of the treatment's efficacy and safety, concluding the participant's involvement in the trial.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. The **experimental medication** under investigation is CLU-RX-BET, which is a **solution for injection** containing the active substance **birch pollen allergoid glutaraldehyde modified**. This substance is classified as a structurally diverse allergen. The trial includes three different dosage levels of CLU-RX-BET: low dose, mid dose, and high dose. Each dosage is administered via **subcutaneous injection**. The maximum daily dose for each variant is 0.7 ml, with a total maximum dose of 6.2 ml over a treatment period of up to 50 weeks. The pharmaceutical form for all dosages is a solution for injection, and the product is manufactured by ROXALL MEDIZIN GMBH.

The non-experimental treatment used in this study is a **placebo preparation**. This placebo is designed for subcutaneous use and is identical in appearance, smell, taste, and excipients to the verum, but it does not contain the active substance, i.e., the allergen extract. The placebo serves as a comparator to evaluate the efficacy and safety of the experimental medication. The administration route for the placebo is also subcutaneous, ensuring consistency in the method of delivery across all treatment arms of the trial.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to establish the most effective and best-tolerated dose of CLU-RX-BET in terms of benefit-risk balance and the Combined Symptom and Medication Score (CSMS). The study is conducted in accordance with regulatory standards and ethical guidelines to ensure the safety and well-being of all participants.

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 Birch Pollen Period (PBPP) for each active treatment group compared to the placebo group. Secondary endpoints will 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 will be evaluated, along with Global Rhinoconjunctivitis Discomfort using a 10.0-point Visual Analogue Scale (VAS).

Further assessments will involve changes in the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores between active and placebo groups, comparing baseline and post-treatment results. The trial will also calculate the percentages of well and severe days, defined by specific criteria related to symptom scores and medication use, during PBPP and BPS. Symptom-free days will be identified as days without symptoms or rescue medication, expressed as a percentage of days during these periods. The titrated Nasal Provocation Test (tNPT) will be used to evaluate the efficacy of each dose of CLU-RX-BET compared to placebo, based on changes in dosing steps required to provoke a positive response. The safety and tolerability of each dose will be analyzed by monitoring Treatment-Emergent Adverse Drug Reactions (TEADR) and the number of patients affected in each group.