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.

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. Methodology: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 log10 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.

Chlorpheniramine Intranasal Spray to Accelerate COVID-19 Clinical Recovery in an Outpatient Setting: The ACCROS Trials

“…Early intervention to treat COVID-19 has been recognized as a strategy for reducing hospitalization and mortality [7,8]. CPM is an effective intranasal agent to address SARS-CoV-2 infection early in the course of the disease (viremic phase) when symptoms are usually mild [6,7,[9][10][11]. Faster recovery will allow individuals to return to daily life quicker, reducing economic stress, healthcare overutilization, and medical centers over ow during outbreaks.…”

“…For instance, antiviral therapies, monoclonal antibody treatments, and steroids have been accepted as standards of care for COVID-19. Evidence suggests that EMT of symptomatic high-risk COVID-19 patients, with both oral and intranasal antihistamines, reduces fatality rate and hospitalizations [9][10][11][12]. A recent study showed that EMT in nursing homes could dramatically reduce hospitalization rates and improve survival [6].…”

Small molecules targeting endolysosomal acidification and signaling in sepsis and severe SARS-CoV-2 infection/COVID-19

“…Trapping and enrichment results in an increase in lysosomal pH from 4.5-5 to 6-6.5 [102] and an inactivation of lysosomal enzymes through a lysosomal pH beyond their optimum pH range (pH 4.5-5.5). Various well-known approved drugs such as ambroxol, amitriptyline, chlorpromazine, desipramine, desloratadine, fluvoxamine, hydroxychloroquine, and azelastine (Figure 2) or the small molecule model compound NB 06 have been classified as lysosomotropic compounds [22,100,[128][129][130][131][132][133][134]. The pivotal involvement of the lysosome in metabolism, endocytosis, and exocytosis renders it an interesting therapeutic target.…”

“…Therefore, it is natural to test azelastine placebo-controlled for its antiviral and viral load-lowering characteristics. After the preliminary evaluation, 0.1% azelastine nasal spray treatment decreased viral load, in particular in patients with initial high viral load and turning negative much faster than in the placebo group [134]. In all these successfully applied small molecules with various indications, lysosomotropism is a common feature [22,129,130,169] that was not necessarily a consideration in the selection process.…”

“…Accumulation in pulmonary tissue is given at a ratio r > 1[135,136]; (B) H 1 -antihistamines and candidates for (systemic) prophylaxis of viral infection and transition to severe SARS-CoV-2 infection/COVID-19. Azelastine (*, green) is a nasal and ophthalmic H 1 -antihistamine over-the-counter (OTC) drug with confirmed lysosomotropism and anti-SARS-CoV(-2) efficacy[134]. Bromhexine, ambroxol, loratadine, desloratadine, azelastine, clemastine, dimethindene, and diphenhydramine are likewise OTC drugs and are easily accessible; (C) various commonly used cardiovascular drugs and the bronchodilator salmeterol.…”