COVID-19: Azelastine nasal spray Reduces Virus-load In Nasal swabs (CARVIN). Early intervention with azelastine nasal sprays reduces viral load in SARS-CoV-2 infected patients. First report on a double-blind placebo-controlled phase II clinical trial. (preprint)

ABSTRACT

Background: The current COVID-19 pandemic has had a major influence on our daily lives. The most frequent early symptoms associated with SARS-CoV-2 infection are coughing, fever, rhinitis, and loss of smell and taste. If the infection progresses to the lower respiratory tract, it can cause massive inflammation of the pulmonary system, which can be life threatening. There is urgent need for a broadly available and effective therapy for the treatment of early infections with SARS-CoV-2 in order to prevent progression to severe disease. Method: ology CARVIN is a phase II proof of concept, randomized, parallel, double-blind, placebo-controlled, interventional clinical trial. 90 SARS-CoV-2 positive volunteers were randomized into three groups to receive either placebo, azelastine 0.02% or azelastine 0.1% nasal spray for a period of 11 days. Seven nasopharyngeal swabs were taken during this period for quantitative PCR measurements assessing the viral load via the ORF 1a/b and E genes. Investigators also assessed patients’ status continuously throughout the trial, and the intensity of individual symptoms were reported by the patients using an electronic diary. Two safety follow-ups were performed at days 16 and 60 of study participation. Results: Since the data of the primary outcome did not show a normal distribution, all statistical tests presented here were done non-parametrically and all p-values are descriptive and without adjustment for multiple testing. A broader descriptive analysis will be performed at a later date on all variables and it will be published in a peer-reviewed publication. A wide range of initial viral loads in the nasopharyngeal swabs of the study population was observed with an overall median/mean + SD Ct value of approximately 21.9 / 23.6 + 5.8, corresponding to log 10 6.6 + 1.8 copies per /ml. Out of the 90 enrolled subjects, at least 54 carried the Alpha (B.1.1.7, UK) variant.Treatment with azelastine nasal sprays resulted in a greater but non-significant decrease in mean viral load compared to that measured in the placebo group at all 6 timepoints after initiation of treatment. This tendency was stable and most pronounced on day 8 (after 7 days treatment), when in the 0.1% and 0.02% azelastine nasal spray groups, an approximately 8- and 29-fold greater clinically meaningful reduction of the baseline viral load, respectively, compared to placebo was observed (based on the ORF1a/b gene). On days 4 and 11, approximately 4-fold greater mean viral load reduction was seen in the 0.1% azelastine group.Differences in mean viral load compared to baseline values were seen starting on the second day (after one day of treatment) in the azelastine 0.1% and azelastine 0.02% group for ORF 1a/b gene, and with azelastine 0.1% for the E gene, while this reduction was less pronounced in the placebo group.The effects of 0.1% azelastine nasal spray treatment to accelerate viral load reduction were even more pronounced in patients with initial high viral load (subgroup analyses in patients exhibiting initial Ct values below 25 and below 20, respectively). Of note, by day 8 the PCR-test had turned negative in more patients in the 0.1% azelastine group (n=6, p= 0.01 for the ORF 1a/b gene and n = 3, p= 0.08 for the E gene) and in the 0.02% azelastine group (n=8, p< 0.01 for the ORF 1a/b gene and n = 5, p= 0.02 for the E gene) than in the placebo group (n=0 for the ORF 1a/b gene and n = 0, for the E gene). Discussion: This study provides the first clinical hints of the effects of an azelastine nasal spray in SARS-CoV-2 positive patients. Subgroup analyses performed in patients exhibiting high initial viral loads are further suggestive of azelastine’s potential as an antiviral treatment.