Purpose: Our group demonstrated the safety, efficacy, and antiviral effect of intranasally administered Chlorpheniramine Maleate (CPM) for treating coronavirus disease 2019 (COVID-19). Since the nasal cavity is the portal of entry for COVID pathogens, sensory and upper respiratory symptoms (URS) (e.g., cough, ageusia, anosmia, nasal congestion, etc.) are significant symptoms in the course of the disease. Intranasal therapies could alleviate the disease-induced URS faster. This study evaluated the effectiveness and safety of intranasal CPM for treating mild to moderate COVID-19-induced URS in the outpatient setting. Methods: The two-part Accelerating COVID-19 Clinical Recovery in an Outpatient Setting (ACCROS) research study was conducted to collect evidence from a randomized, double-blinded placebo-controlled trial (ACCROS-I). Both parts enrolled patients with mild to moderate COVID-19 confirmed by reverse transcription-polymerase chain reaction. The primary endpoint in ACCROS-I was time to clinical recovery, defined as the change from baseline to day 7 in COVID-19 symptoms reported as the percent change (Δ%) in the daily symptoms score (DSS) and the severity of the disease symptoms using a visual analog scale (VAS), on a scale of 1-10 (10=worst symptoms). COVID-19 patients (n = 101) were recruited and assigned to either a 10-day CPM treatment (n=61) or placebo (PLB) (n=40) in addition to standard of care (SoC). Secondary endpoints included the incidence of hospitalization and the proportion of patients with URS on day 7. ACCROS-II data were collected from medical records of COVID-positive subjects using a standardized form. Cohorts of patients treated with CPM and SoC (CPM+Soc) were compared for the duration of general symptoms and URS. Patient information was collected as part of routine visits and telehealth consultations. Results ACCROS-I: There was a statistically significant difference in the rate of clinical recovery (P<0.05) in Δ%DSS (M -18.8±SEM 7.9%) and Δ%VAS (-8.6±5.1%), such that the CPM group reported fewer symptoms than PLB. The proportion of patients who reported sensory deficits and URS at day 7 was significantly lower (P<0.05) in CPM vs. PLB for ageusia (1.7% vs. 15.0%), cough (16.4% vs. 35.0%) and nasal congestion (8.1%vs.20%). None of the patients required hospitalization. ACCROS-II: There was a statistically significant reduction (P<0.05) in total days reporting URS for general symptoms of COVID-19 in CPM+SoC (5.1 ± 0.1) compared to SoC (11.0 ± 0.2). CPM+SoC users also showed fewer days with cough, anosmia, and ageusia. Persistent anosmia (over 29 days) was found in 3% of the patients on SoC, whereas no persistent anosmia was reported in the CPM+SoC cohort (X2 = 10.18; P<0.001). Conclusion: The result of this two-part study supports the conclusion that intranasal CPM is an antiviral agent that can be administered intranasally to treat COVID-19-induced symptoms effectively. Intranasal CPM accelerates clinical recovery and reduces URS in patients with mild to moderate COVID-19. This study's important implications include individuals returning to daily life faster, reducing community and individual economic burden, and decreasing healthcare utilization. Trial registration: ClinicalTrials.gov.; ID: NCT05449405 ACCROS-I retrospectively registered on 7/13/2022, NCT05520944 ACCROS-R retrospectively registered on 08/27/2022.

Acute viral pharyngitis (AVP) is a common respiratory illness affecting many individuals. Despite symptomatic treatment management of AVP, therapies are lacking to target a broad spectrum of viruses and the inflammatory nature of the disease. Available for many years, Chlorpheniramine Maleate (CPM), is considered a low-cost and safe first-generation antihistamine displaying antiallergic, anti-inflammatory, and as of recently, identified as a broad-spectrum antiviral agent with activity against influenzas A/B viruses and SARS-CoV-2. Efforts have been made to identify repurposed drugs with favorable safety profiles that could significantly benefit the treatment of COVID-19-induced symptoms. The present case series highlights three patients in which a CPM-based throat spray was used to alleviate the symptoms of COVID-19-induced AVP. The CPM throat spray was associated with significant improvements in patient symptoms after approximately three days of use as opposed to the typical five to seven days reported elsewhere. While AVP is a self-limited syndrome and usually improves without pharmaceutical therapy, CPM throat spray may significantly reduce the overall time that the patient has symptoms. Additional clinical studies to evaluate the efficacy of CPM for the treatment of COVID-19-induced AVP are warranted.