Efficacy and Safety Evaluation of Subcutaneous Cluster Immunotherapy with Allergenic Extract of Olea Europaea Pollen 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 **CLUSTOID®/CLUXIN® Olea europaea** in patients with moderate-to-severe allergic rhinitis or rhinoconjunctivitis due to olive pollen. This is assessed in terms of 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 this specific allergy.

The clinical trial involves a total of **510 participants** diagnosed with **moderate-to-severe allergic rhinitis/rhinoconjunctivitis** due to olive pollen, as per the Allergic Rhinitis and its Impact on Asthma (ARIA) guideline. The study population comprises both male and female subjects aged between **18 and 65 years**. Participants were selected based on their medical history of allergic rhinitis/rhinoconjunctivitis 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 does not include a vulnerable population. Participants are required to have a forced expiratory volume (FEV1) in one second greater than 80% of the predicted normal value if they have asthma. Sensitization to Olea europaea pollen was confirmed through a positive skin prick test and serum allergen-specific IgE levels. The trial population is expected to maintain compliance with the study protocol, including the use of an electronic diary for self-evaluation of symptoms and rescue medication. Safety laboratory results must be within normal ranges or deemed not clinically significant. The sponsor has not provided specific information regarding lifestyle considerations such as diet or physical activity.

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 olive pollen. This is a Phase II-III, randomized, double-blind, placebo-controlled study. The trial aims to establish the most effective and best-tolerated dose of CLUSTOID®/CLUXIN® Olea europaea, focusing on the benefit-risk balance and the Combined Symptom and Medication Score (CSMS). The trial is expected to commence on September 2, 2024, and conclude by September 30, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, medical history, and sensitization to **Olea europaea** pollen. The trial will include multiple follow-up visits to monitor the participants' response to treatment and any adverse effects. The end-of-study visit will assess the overall outcomes and gather final data. The expected duration of participant involvement is up to 378 days, depending on the treatment group assignment.

Participants may be withdrawn from the study early if they experience significant adverse reactions, fail to comply with study procedures, or withdraw consent. The primary endpoint is the absolute difference in mean CSMS during the Peak Olive Pollen Period (POPP) between active treatment and placebo groups. Secondary endpoints include differences in mean CSMS during other periods, symptom-free days, and safety assessments through Treatment-Emergent Adverse Drug Reactions (TEADR).

The clinical trial involves several treatments, including both experimental and non-experimental medications. The experimental medication, **CLU-RX-OLE**, is an allergenic extract of **Olea europaea** pollen polymerized with glutaraldehyde. It is available in three dosage forms: high dose, mid dose, and low dose. The pharmaceutical form is a solution for injection, administered via transdermal use. The maximum daily dose is 0.7 ml, with a total maximum dose of 4.7 ml over a treatment period of 48 weeks. Participant compliance is monitored through regular assessments of symptom and medication scores.

Another experimental treatment is **Mometasona cinfa 50 microgramos/pulverización**, a nasal spray suspension containing **mometasone furoate**. This medication is administered as a nasal spray, with a maximum daily dose of 0.1 mg and a total maximum dose of 37.8 mg over a treatment period of 378 days. Compliance is ensured through participant diaries and regular follow-up visits.

The trial also includes a placebo preparation for subcutaneous use, designed to mimic the appearance, smell, taste, and excipients of the active treatment without containing the active allergen extract. This placebo is used to maintain blinding and assess the efficacy of the experimental treatments.

Non-experimental treatments include **Prednisona CINFA 10 mg comprimidos**, a tablet form of **prednisone**. This medication is administered orally, with a maximum daily dose of 10 mg and a total maximum dose of 3.78 g over 378 days. Participant adherence is monitored through pill counts and patient diaries.

Additionally, **Loratadina Kern Pharma 10 mg comprimidos EFG** and **loratadina cinfa 10 mg comprimidos EFG** are included as standard-of-care therapies. Both are tablet forms of **loratadine**, administered orally with a maximum daily dose of 10 mg and a total maximum dose of 3.78 g over 378 days. Compliance is tracked through patient self-reports and regular check-ins.

Auxiliary treatments include various solutions for skin-prick tests, such as **Prick Test LETI Negativkontrolle Pricktestlösung** containing **sodium chloride**, and **Prick Test Histamin LETI Positivkontrolle** containing **histamine dihydrochloride**. These are used for diagnostic purposes and are administered transdermally in single drop doses.

Other auxiliary treatments include solutions for provocation tests, such as **Provokations-Testlösung Esche 5.000 BE/ml Lyophilisat und Lösungsmittel**, containing **ash**. This is administered nasally in drop form, with a maximum daily dose of 5 drops and a total maximum dose of 8 drops over 2 days.

Throughout the trial, participant compliance and response to treatments are closely monitored through a combination of self-reported diaries, regular clinical assessments, and objective measures of symptom and medication scores. This comprehensive approach ensures accurate evaluation of the efficacy and safety of the treatments under investigation.

The efficacy of the clinical trial will be assessed using the primary endpoint, which is the absolute difference in mean **CSMS** (Combined Symptom and Medication Score) during the Peak Olive Pollen Period (POPP) between each active treatment group and the placebo group. Secondary endpoints include absolute and relative differences in mean CSMS during the Olive Pollen Season (OPS), mean daily Symptom Score (dSS), and mean daily Medication Score (dMS) during both POPP and OPS. Additional assessments 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, as well as symptom-free days during the POPP and OPS.

The trial will also evaluate the efficacy of each dose of CLU-RX-OLE compared to placebo using the titrated Nasal Provocation Test (tNPT). This will be defined by the percentage of patients with an increased dosing step and the change in the number of dosing steps needed to provoke a positive response in the tNPT post-treatment compared with pre-treatment. The safety and tolerability of each dose will be analyzed by monitoring Treatment-Emergent Adverse Drug Reactions (TEADR) and the number of patients affected by TEADRs in each group.