Efficacy and Safety Evaluation of Phleum Pratense Pollen Extract Sublingual Immunotherapy in Patients with Moderate-to-Severe Grass 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 Phleum pratense** in patients with moderate-to-severe allergic rhinitis or rhinoconjunctivitis due to grass 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 for individuals suffering from grass pollen allergy, potentially improving their quality of life by reducing symptoms and medication use.

The clinical trial involves a total of **482 participants** who have been diagnosed with **moderate-to-severe allergic rhinitis/rhinoconjunctivitis** due to grass pollen, as per the Allergic Rhinitis and its Impact on Asthma (ARIA) guideline. The study population comprises both **female and male** 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 70% of the predicted normal value if they have asthma. Sensitization to Phleum pratense pollen was confirmed through a positive skin prick test, serum allergen-specific IgE levels, and a positive response to nasal provocation. The trial population was selected based on their ability to comply with study requirements, including the use of an electronic diary for self-evaluation of symptoms and medication. 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 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 establish the most effective and best-tolerated dose of SULGEN® Spray Phleum pratense, focusing on the benefit-risk balance and the Combined Symptom and Medication Score (CSMS). The trial is expected to commence on November 6, 2023, and conclude by October 30, 2025, with an estimated duration of 340 days for each participant.

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 Phleum pratense pollen. The inclusion criteria require patients to have a history of allergic rhinitis or rhinoconjunctivitis for at least two years, with or without well-controlled mild-to-moderate asthma. Following the screening, eligible participants will be randomized into treatment groups receiving either the active treatment or placebo. The trial will include regular follow-up visits to monitor safety, efficacy, and compliance, with assessments such as skin prick tests and nasal provocation tests. The end-of-study visit will evaluate the overall outcomes and any adverse events.

Participant involvement is expected to last for the entire trial duration unless early termination is warranted. Conditions for early termination include non-compliance with study procedures, withdrawal of consent, or any adverse events deemed significant by the study investigators. The primary endpoint is the absolute difference in mean CSMS during the Peak Grass Pollen Period (PGPP) between active and placebo groups. Secondary endpoints include differences in CSMS during the Grass Pollen Season (GPS), changes in Rhinoconjunctivitis quality of life, and the percentage of well and severe days. The trial will also assess the efficacy of each dose of SULGEN® Spray Phleum pratense compared to placebo using titrated Nasal Provocation Tests (tNPT).

The clinical trial involves several treatments, including experimental and non-experimental medications. The **SULGEN® Spray Phleum pratense** is an experimental sublingual spray solution containing **Phleum pratense pollen extract**. It is administered sublingually at a mid-dose of 0.2 ml per day, with a maximum total dose of 68 ml over a treatment period of 340 days. The spray is designed to assess the efficacy and safety of sublingual immunotherapy in patients with grass pollen allergy.

Another experimental treatment is the **SULGEN® Spray Phleum pratense low dose**, which also contains **Phleum pratense pollen extract**. This sublingual spray is administered at a low dose of 0.2 ml per day, with the same maximum total dose and treatment period as the mid-dose formulation. The purpose is to determine the optimal dose for balancing efficacy and safety.

The trial also includes a **sublingual placebo preparation** that mimics the appearance, smell, taste, and excipients of the active treatment but lacks the active allergen extract. This placebo is used to compare the effects of the active treatment against a non-active control.

Non-experimental treatments include **MometaHEXAL Heuschnupfenspray**, a nasal spray suspension containing **mometasone furoate**. It is administered as a nasal spray with a daily dose of 0.1 mg, reaching a maximum total dose of 34 mg over 340 days. This auxiliary treatment is used to manage symptoms of allergic rhinitis.

**Prednisolon AL 10 mg Tabletten** is another auxiliary treatment, containing **prednisolone**. It is administered orally at a daily dose of 10 mg, with a maximum total dose of 3.4 g over the treatment period. This corticosteroid is used to manage inflammation and allergic reactions.

Additionally, **Lorano akut, 10 mg Tabletten** containing **loratadine** is used as an auxiliary treatment. It is administered orally at a daily dose of 10 mg, with a maximum total dose of 3400 mg over 340 days. Loratadine is an antihistamine used to relieve allergy symptoms.

Several skin-prick test solutions are used as auxiliary treatments to assess allergic responses. These include solutions containing extracts from various allergens such as **timothy grass pollen**, **artemisia vulgaris**, **alternaria alternata**, **felis domesticus**, **canis familiaris**, **betula verrucosa**, **ambrosia artemisiifolia**, and **dermatophagoides pteronyssinus**. Each solution is administered topically as a single drop per test, with a maximum of one drop per day.

Control solutions for skin-prick tests include **ALK-prick Positiv-Kontrolle** and **Prick Test Histamin LETI Positivkontrolle**, both containing **histamine dihydrochloride**. These are used to confirm the skin's reactivity during testing. Additionally, **Prick Test LETI Negativkontrolle** and **ALK-prick Negativ-Kontrolle** containing **sodium chloride** are used as negative controls to ensure the accuracy of the test results.

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 Grass Pollen Period (PGPP) of each active treatment group compared to the placebo treatment group. Secondary endpoints include absolute and relative differences in mean CSMS during the Grass Pollen Season (GPS) between active and placebo treatment groups, as well as differences in mean daily Symptom Scores (dSS) and daily Medication Scores (dMS) during PGPP and GPS. 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 calculation of well and severe days based on specific criteria. Symptom-free days will also be evaluated as a percentage of days during the PGPP and GPS.

The trial will further assess the efficacy of each dose of SULGEN® Spray Phleum pratense compared to placebo using the titrated Nasal Provocation Test (tNPT). This will be defined as 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 efficacy parameters will be measured and collected at specified timepoints throughout the trial, ensuring a comprehensive analysis of the treatment's impact on patients with grass pollen allergy.