Safety and Efficacy of Small Extracellular Vesicles Nebulizer in Patients With Allergic Rhinitis Complicated With Asthma

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).

Inclusion criteria

• Aged 18-60 years, regardless of gender;
• Patients with moderate to severe allergic rhinitis (with sleep/work/study/daily activity impairment or distressing symptoms) meeting the diagnostic criteria of the international Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines, positive for at least one inhalant allergen skin prick test, and concurrent asthma complying with the Global Initiative for Asthma (GINA) 2022 guidelines;
• Suboptimal response to antiallergic medication treatment for one year prior to enrollment;
• Patients who decline allergen-specific immunotherapy, or have no available specific therapy for the relevant allergen, or failed allergen-specific immunotherapy;
• Females of childbearing potential must agree to avoid pregnancy during study participation and for 30 days after the final visit;
• Subjects or their legal representatives must be able to sign the informed consent form and comply with the study requirements for medication administration and follow-up.

Exclusion criteria

• Complicated with other nasal and sinus diseases that may affect the reasonable assessment of efficacy and/or safety;
• Suffering from uncontrolled asthma or poorly controlled asthma symptoms;
• Suffering from malignant tumors, severe immune diseases, long-term use of immunosuppressants, or immunodeficiency;
• Having unstable conditions due to respiratory tract infection and/or acute asthma exacerbation within 4 weeks prior to the initial screening visit;
• Currently receiving treatment with beta-blockers or angiotensin-converting enzyme (ACE) inhibitors;
• Suffering from mental illnesses;
• Suffering from severe systemic diseases, such as cases of peptic ulcers, diabetes mellitus, and heart failure;
• Specific infections such as syphilis, leprosy, and tuberculosis;
• Females who are currently pregnant, planning to become pregnant soon, or breastfeeding;
• Patients who are currently participating in other clinical trials or have participated in other clinical trials within 30 days prior to the initial screening visit;
• Patients who are currently receiving allergen desensitization therapy or biologic therapy;
• Positive for hepatitis B surface antigen, hepatitis C virus antibody, syphilis serological antibody, or human immunodeficiency virus (HIV) antibody;
• In addition to the above conditions, patients will be excluded if the investigators consider them unsuitable for participation in this clinical study for other reasons.