Results from a phase 2, double-blind, placebo-controlled, single-center trial suggest that azelastine nasal spray may reduce the incidence of respiratory infections caused by SARS-CoV-2.1
“Although vaccines have dramatically reduced the severity of COVID-19, there remain limited pharmacological options for preventing infection itself,” said corresponding author Robert Bals, MD, PhD, from the Department of Internal Medicine at Saarland University Hospital in Homburg, Germany. “Preexposure prophylaxis is particularly relevant for high-risk groups and during times of high viral exposure. Azelastine, an established over-the-counter antihistamine nasal spray, has shown promising in vitro antiviral activity. Our study aimed to test, in a controlled clinical setting, whether this could reduce the risk of SARS-CoV-2 infection.”
In the study published in JAMA Internal Medicine, Dr. Bals and colleagues at Saarland University Hospital randomly assigned 227 participants to apply one puff (0.14 mL) per nostril of azelastine 0.1% nasal spray three times per day and 223 participants to apply one puff per nostril of a placebo spray three times per day for a mean duration of 56 days. The primary end point was the development of SARS-CoV-2 infection (including asymptomatic cases) through day 56, as measured by twice-weekly rapid antigen testing and confirmed by polymerase chain reaction (PCR) testing.
Two-thirds of study participants were female; their mean age was 33 years, and 93% were White. In the intention-to-treat population used for the primary analysis, the incidence of PCR-confirmed SARS-CoV-2 infection was significantly lower in the azelastine group (five of 227 participants [2.2%]) compared with the placebo group (15 of 223 participants [6.7%]) (risk difference, -4.5 percentage points; 95% CI, -8.3 to -0.7; P = .02). This corresponded to an OR of 0.31 (95% CI, 0.11-0.87). Similar findings were observed in the per-protocol analysis, which included 353 participants who adhered to the study protocol without major deviations.
Among the secondary end points, compared with placebo, azelastine was associated with a longer mean time to SARS-CoV-2 infection among infected participants (31.2 [9.3] vs 19.5 [14.8] days), a reduced number of PCR-confirmed symptomatic infections (9.3% [21 of 227 participants] vs 22.0% [49 of 223 participants]), and a lower incidence of PCR-confirmed rhinovirus infections (1.8% vs 6.3%). The overall incidence of adverse events was similar between the two groups. Two serious adverse events occurred in the azelastine group; however, neither was considered related to the treatment.
“This study highlights that repurposing well-known, widely available medications can yield promising new preventive strategies,” Dr. Bals said. “Azelastine nasal spray is not a substitute for vaccination, but it may become an additional tool to reduce infection risk. We view this as a starting point, a signal of efficacy that now warrants confirmation in larger phase 3 trials.”
He noted that several questions remain unanswered, including: Will these findings be confirmed in multicenter cohorts with more diverse populations? How effective is azelastine prophylaxis in individuals who are immunocompromised or older? What is the optimal dosing regimen and duration for real-world protection? Does azelastine confer protection against other respiratory pathogens?
The authors acknowledged certain limitations of the analysis, including the modest sample size, the single-center design, and the predominance of a healthy, vaccinated study population.
“Finally, the bitter taste of azelastine could have partially unblinded participants, potentially introducing bias,” Dr. Bals said.
References
1. Lehr T, Meiser P, Selzer D, et al. Azelastine nasal spray for prevention of SARS-CoV-2 infections: a phase 2 randomized clinical trial. JAMA Intern Med. Published online September 2, 2025. doi:10.1001/jamainternmed.2025.4283
