Single-center randomized trial shows lower infection rates and extended time to SARS-CoV-2 infection, though larger studies are needed to confirm findings.
Robert Bals, MD, PhD, FERS
Image credits: Saarland University Hospital
Azelastine nasal spray was associated with a significantly reduced risk of laboratory-confirmed SARS-CoV-2 infections in a phase 2 randomized clinical trial published September 2, 2025, in JAMA Internal Medicine. Investigators reported that the spray reduced SARS-CoV-2 respiratory infections and may serve as a safe prophylactic intervention, though confirmation in larger multicenter trials is needed.1
The double-blind, placebo-controlled, single-center study enrolled 450 healthy adults at Saarland University Hospital in Germany between March 2023 and July 2024. Participants were randomized 1:1 to receive azelastine, .1%, nasal spray (n = 227) or placebo (n = 223), administered 3 times daily for 56 days. Twice-weekly SARS-CoV-2 rapid antigen testing was conducted, with positive results confirmed by polymerase chain reaction (PCR). Symptomatic participants with negative rapid antigen tests underwent multiplex PCR for respiratory viruses.1
In the intention-to-treat analysis, the incidence of PCR-confirmed SARS-CoV-2 infection was significantly lower in the azelastine group (5 of 227 (2.2%) compared with placebo (15 of 223 (6.7%) (odds ratio, .31; 95% CI, .11-.87). The mean (SD) time to SARS-CoV-2 infection among infected participants was longer with azelastine than placebo (31.2 [9.3] vs 19.5 [14.8] days). Azelastine also reduced PCR-confirmed symptomatic infections (21 vs 49) and lowered incidence of PCR-confirmed rhinovirus infection (1.8% vs 6.3%).1
In the intention-to-treat analysis, SARS-CoV-2 infections occurred in 2.2% of the azelastine group vs 6.7% of placebo (OR, .31; 95% CI, .11-.87).
Azelastine use was linked to a longer mean time to infection (31.2 vs 19.5 days) and fewer PCR-confirmed symptomatic infections (21 vs 49).
The spray also reduced rhinovirus infections (1.8% vs 6.3%), with adverse events comparable between groups.
According to investigators, “the increase in time to SARS-CoV-2 infection indicates that even in times of higher exposure rates, fewer infections per exposure occurred under treatment compared with placebo. Together, these findings reinforce the potential of azelastine nasal spray to meaningfully reduce infection risk in a prophylactic setting.”1
Baseline demographics showed a mean (SD) age of 33.0 (13.3) years; 66.4% of participants were female, and 92.7% were White. Adverse events occurred at similar rates between groups.1
The study’s limitations included its modest sample size, single-center design, and a largely healthy, vaccinated population, which may restrict generalizability. Additional concerns were potential unblinding due to azelastine’s bitter taste, possible prophylactic effects of the placebo, and underreporting of asymptomatic or non–SARS-CoV-2 infections due to testing protocols.1
To place the trial findings into clinical context, Contagion spoke with investigator Professor Robert Bals, MD, PhD, FERS, from Saarland University Hospital. In the following email Q&A, he discussed the implications of the phase 2 trial and what comes next for azelastine nasal spray research.
Contagion: Given the trial’s single-center design and relatively young, homogeneous population, what are the main considerations in applying these findings to other age groups or higher-risk cohorts?
Bals: "Our investigation was a single-center study in a predominantly young, healthy, and vaccinated population. The findings provide a strong proof-of-concept, but generalizability to older adults, immunocompromised patients, or those with comorbidities requires caution. Larger and more diverse trials are needed to confirm safety and efficacy in specific patient groups."
Contagion: With reductions observed in both SARS-CoV-2 and rhinovirus infections, what mechanisms at the mucosal level might best explain azelastine’s activity?
Bals: "The nasal mucosa is the primary site of viral entry. Azelastine acts locally, where several mechanisms may contribute: stabilization of the epithelial barrier, interference with viral docking via ACE2, inhibition of the SARS-CoV-2 protease, and suppression of ICAM-1, a key rhinovirus receptor. Together these mechanisms likely reduce the chance of successful viral replication and spread at the portal of entry."
Contagion: Looking ahead, what types of larger or multicenter studies would be most important to confirm and expand on these Phase 2 findings?
Bals: "The next step should be multicenter, randomized phase 3 trials including larger, more heterogeneous populations across age groups and risk categories. Such studies should also examine efficacy against multiple circulating respiratory viruses, and stratify results by vaccination status, prior infection, and underlying diseases."
According to the Mayo Clinic, azelastine nasal spray is an FDA-approved antihistamine used for seasonal and perennial allergic rhinitis and other upper respiratory allergies. By blocking histamine, it helps relieve nasal congestion, sneezing, itching, and runny nose. The drug has been available for decades, is generally well tolerated, and is now being investigated for potential antiviral benefits, including activity against SARS-CoV-2.2
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