Safety and Preliminary Efficacy of Small Extracellular Vesicles (Code: hUC-MSC-sEV-002) Nebulizer in Patients With Allergic Rhinitis Complicated With Asthma: A Multicenter, Prospective, Randomized, Double-Blind Phase I/II Clinical Study

Allergic rhinitis is an independent risk factor for asthma. As inflammatory disorders affecting the upper and lower airways respectively, allergic rhinitis and asthma share similar pathogenesis and interact with each other, thus being recognized as "one airway, one disease". Their incidence rates are increasing year by year with a wide distribution, and they often coexist. These conditions have become an important issue affecting people's quality of life worldwide and imposed a heavy economic burden on society. In the treatment of allergic rhinitis complicated with asthma, glucocorticoids, antihistamines, leukotriene receptor antagonists and other agents are the most commonly used drugs. However, long-term use of these drugs is prone to induce various adverse reactions. Moreover, drug resistance and intolerance observed in some patients have also limited the widespread application of these medications. Therefore, there is an urgent need for novel therapeutic approaches for allergic diseases.

Small extracellular vesicles derived from mesenchymal stem cells not only possess immunomodulatory functions similar to those of mesenchymal stem cells, but also exhibit more advantages in clinical applications, including no tumorigenic risk, small size, stable performance, easy transportation and preservation, low immunogenicity, and the ability to penetrate biological barriers. Therefore, they hold great potential and broad application prospects in the treatment of allergic rhinitis complicated with asthma.

This is a multicenter, prospective, randomized, double-blind, placebo-controlled, dose-finding clinical trial, designed to evaluate the safety and preliminary efficacy of nebulized human umbilical cord blood mesenchymal stem cell-derived small extracellular vesicles (code: hUC-MSC-sEV-002) in the treatment of allergic rhinitis complicated with asthma. The trial consists of two phases, namely the dose-finding phase (Phase I clinical trial) and the cohort expansion phase (Phase II clinical trial). It encompasses three study periods: the screening period (Visit 0, Weeks -2 to 0), the treatment period (Visit 1, Week 2), and the follow-up period (Visit 2, Week 4; Visit 3, Week 12; Visit 4, Week 24). The scheduled visit plan includes baseline assessment, the end of Week 2, the end of Week 4, Week 12, and Week 24.

Primary safety endpoints include dose-limiting toxicities (DLT) associated with nebulized hUC-MSC-sEV-002, covering the following aspects: the incidence of drug-related adverse reactions occurring within the short-term post-treatment period (0 to 24 hours); the incidence of drug-related adverse reactions within 2 weeks of treatment; changes in vital signs, complete blood count plus C-reactive protein (CRP), urine routine, liver and kidney function, immune profile panel (IgG, IgA, IgM, C3, C4), and electrocardiogram (ECG) from baseline to the end of Week 2 of treatment.

Secondary safety endpoints include the incidence of adverse events at Week 12 and Week 24 of treatment; changes in vital signs, complete blood count, urine routine, liver and kidney function, immune profile panel, and electrocardiogram (ECG) from baseline to Week 12 and Week 24 of treatment; pulmonary function tests at Week 2 and Week 24 of treatment; and chest X-ray examination at Week 24 of treatment.

Questionnaire (RQLQ) scores, Total Nasal Symptom Score (TNSS), Visual Analog Scale (VAS) scores, Asthma Control Test (ACT) scores, forced expiratory volume in one second (FEV₁), and peak expiratory flow (PEF) at Week 24 of treatment.

Secondary efficacy endpoints include the percentage changes from baseline in the Rhinitis Quality of Life Questionnaire (RQLQ) scores, Total Nasal Symptom Score (TNSS), and Visual Analog Scale (VAS) scores at the end of Week 2, end of Week 4, and Week 12 of treatment; the percentage changes from baseline in forced expiratory volume in one second (FEV₁), peak expiratory flow (PEF), and Asthma Control Test (ACT) scores at the end of Week 2, end of Week 4, and Week 12 of treatment; the percentage changes from baseline in total serum IgE, specific IgE, and IgG4 levels at Week 12 and Week 24 of treatment; and the changes in nasal endoscopy findings and nasal exhaled nitric oxide test results from baseline to Week 12 and Week 24 of treatment.

Exploratory endpoints include the changes from baseline in plasma cytokines (IFN-γ, IL-6, IL-4, IL-5, IL-13), peripheral blood lymphocytes, and the subsets of Th1, Th2, Th17 and ILC2 at the end of Week 2, Week 12 and Week 24 of treatment; as well as the changes from baseline in nasal secretion cytokines (ECP, IL-6, IFN-γ, IL-5, IL-13, IL-33) at the end of Week 2, Week 12 and Week 24 of treatment.

All adverse events occurring in all subjects during the clinical study shall be monitored closely. The adverse event forms shall be completed in a timely manner, with detailed documentation of clinical manifestations, severity, time of onset, duration, measures taken and clinical outcomes. The study shall not be initiated until the clinical study protocol and the informed consent form have been submitted to and approved by the Institutional Review Board (IRB).