Evaluation of Intralymphatic Immunotherapy Enhanced by Vitamin D in Patients with Moderate to Severe Allergic Rhinitis: A Randomized, Placebo-Controlled Study

The primary objective of this study is to evaluate whether patients with moderate to severe **allergic rhinitis** due to grass pollen, who receive intralymphatic immunotherapy (ILIT) combined with vitamin D, exhibit a clinically significant improvement in the combined symptom and medication score (CSMS) during the pollen season compared to those receiving ILIT without vitamin D. This is clinically relevant as it may offer an enhanced therapeutic strategy for managing allergic rhinitis, potentially improving patient outcomes and quality of life.

The clinical trial involves participants diagnosed with **allergic rhinitis**, specifically targeting individuals with moderate to severe grass allergy symptoms. The study population includes both male and female subjects, aged between 18 and 60 years, who have been verified to have moderate to severe symptoms as per the Rhinoconjunctivitis Total Symptom Score (RTSS >8). Participants were required to provide written consent to partake in the study. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet, physical activity, or other habits have not been specified as part of the study criteria.

The clinical trial is designed as a **randomized**, **placebo-controlled** study to evaluate the efficacy of intralymphatic immunotherapy (ILIT) enhanced with vitamin D in patients with moderate to severe grass pollen allergy, specifically **allergic rhinitis**. The trial will compare the clinical outcomes of ILIT with and without vitamin D supplementation. The primary objective is to assess the improvement in the Combined Symptom Medication Score (CSMS) during the pollen season. The study is expected to run until December 31, 2029, with recruitment having commenced on September 1, 2022.

Participants will be involved in the study for a maximum treatment period of 36 months. The trial includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor progress and collect data, and a final end-of-study visit to assess outcomes. The inclusion criteria require participants to be aged 18-60 years, have a verified grass allergy with moderate to severe symptoms, and provide written informed consent. The primary endpoint is the CSMS during the grass pollen season post-treatment, compared to baseline and placebo group scores. Secondary endpoints include quality of life assessments, nasal symptom scores, and immunological analyses.

Participants may be withdrawn from the study if they experience adverse reactions, fail to comply with the study protocol, or withdraw consent. The trial involves the administration of various products, including **colecalciferol** and **phleum pratense** (225), with routes of administration being intramuscular, sublingual, and subcutaneous. The study is not classified as low intervention and encompasses both phase II and phase III trials. The trial's design ensures rigorous assessment of the therapeutic potential of vitamin D-enhanced ILIT in managing allergic rhinitis.

The clinical trial involves the administration of several treatments, including both experimental and comparator medications. The **experimental medication** is **colecalciferol**, also known as vitamin D3, which is administered intramuscularly. It is provided in a pharmaceutical form identified as PHF00165MIG, with a maximum daily dose of 100,000 IU/ml. The treatment period for colecalciferol is limited to one day. The active substances in this formulation include colecalciferol and glycerol, both of which are of chemical origin.

One of the **comparator treatments** is **GRAZAX**, a sublingual lyophilisate containing the active substance **Phleum pratense** (225), commonly known as Timothy grass pollen. This medication is administered sublingually with a maximum daily dose of 75,000 SQU (Standardised Quality Unit) and a total dose of 82,125,000 SQU over a treatment period of 36 months. The active substance is a structurally diverse allergen, and the product is manufactured by ALK-ABELLO A/S.

Another **comparator treatment** is **Alutard SQ Timotej**, a suspension for injection containing the same active substance, Phleum pratense (225). This medication is administered via subcutaneous injection with a maximum daily dose of 1,000 SQU/ml and a total dose of 3,000 SQU/ml over a treatment period of 21 days. Like GRAZAX, this product is also manufactured by ALK-ABELLO A/S and contains a structurally diverse allergen.

The **placebo** used in the study is **Natriumklorid Braun**, a solution for injection containing **sodium chloride**. It is administered either intramuscularly or intravenously, with a maximum daily dose of 9 mg/ml. The treatment period for this placebo is limited to one day. The sodium chloride solution is of chemical origin and is produced by B.BRAUN MELSUNGEN AG.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of intralymphatic immunotherapy enhanced by vitamin D in patients with moderate to severe grass allergy, comparing the outcomes with those receiving standard sublingual immunotherapy and placebo.

Efficacy in this clinical trial will be assessed using the **Combined Symptom Medication Score (CSMS)** as the primary endpoint. The CSMS will be evaluated during the grass pollen season following treatment and compared to baseline CSMS and the CSMS in the placebo group. Baseline is defined as the pollen season prior to treatment. Secondary endpoints include the CSMS during the peak of the grass pollen season, both before and after treatment, as well as the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), NTS score, and Visual Analogue Scale (VAS), all measured before and after treatment. Additionally, analyses of nasal lavage using flow cytometry, PCR, and ELISA will be conducted to quantify immune cells and Th1/Th2 cytokines before and after treatment. Serum levels of IgE, IgG, IgA, and Th1/Th2 cytokines will also be measured pre- and post-treatment.