Characterization of Inhaled Nitric Oxide (iNO) for the treatment of Viral Community Acquired Pneumonia (CAP)

Background. Nitric Oxide (NO) has been previously demonstrated to have antimicrobial, anti-inflammatory, and vasodilator properties. Extensive work has been done in the clinical setting to explore these properties with iNO administered intermittently at high concentrations of 150-250 ppm. While viral CAP has gained major attention with the emergence of COVID-19, treatment methods remain limited and are challenging to develop. The purpose of this study is to assess iNO treatment administered to hospitalized adults with viral CAP. Methods. This is a randomized, open label multi-center ongoing study. Study population includes subjects aged 18-80, hospitalized for vCAP including COVID-19. Following enrollment, subjects were randomized 1:1 to either iNO [150ppm for 40 minutes, 4 times daily, up to 7 days in addition to standard supportive treatment (SST)], or control [SST alone]. iNO was delivered by LungFitTM, an innovative NO generator under development (Beyond Air, NY, USA). Follow up period is 180 days. Study endpoints include safety and the time to reach a stable saturation of >=93%. In addition, different other clinical parameters are collected to profile the effect of iNO in this population. Results. Analyzing the Intent To Treat (ITT) population (n=35, [16 iNO and 19 control]), safety profile of iNO treatment observed so far, was found to be favorable with no treatment related Adverse Events (AEs). Faster clinical improvement was noted in the iNO treatment group, paralleling CRP improvement between baseline to end of treatment (mean 2.7 mg/dl comparing treatment group [n=8] to control group [n=7], data not final). Conclusion. These data suggest that intermittent treatment with 150ppm iNO is safe and well tolerated and may contribute to faster clinical improvement in viral CAP. Different laboratory parameters may shed some light and help to characterize this observed effect, supporting the further exploration of iNO for the treatment of viral lower respiratory tract infection, including COVID-19.

Effects of training and using an audio-tactile sensory substitution device on speech-in-noise understanding.

Understanding speech in background noise is challenging. Wearing face-masks, imposed by the COVID19-pandemics, makes it even harder. We developed a multi-sensory setup, including a sensory substitution device (SSD) that can deliver speech simultaneously through audition and as vibrations on the fingertips. The vibrations correspond to low frequencies extracted from the speech input. We trained two groups of non-native English speakers in understanding distorted speech in noise. After a short session (30-45 min) of repeating sentences, with or without concurrent matching vibrations, we showed comparable mean group improvement of 14-16 dB in Speech Reception Threshold (SRT) in two test conditions, i.e., when the participants were asked to repeat sentences only from hearing and also when matching vibrations on fingertips were present. This is a very strong effect, if one considers that a 10 dB difference corresponds to doubling of the perceived loudness. The number of sentence repetitions needed for both types of training to complete the task was comparable. Meanwhile, the mean group SNR for the audio-tactile training (14.7 ± 8.7) was significantly lower (harder) than for the auditory training (23.9 ± 11.8), which indicates a potential facilitating effect of the added vibrations. In addition, both before and after training most of the participants (70-80%) showed better performance (by mean 4-6 dB) in speech-in-noise understanding when the audio sentences were accompanied with matching vibrations. This is the same magnitude of multisensory benefit that we reported, with no training at all, in our previous study using the same experimental procedures. After training, performance in this test condition was also best in both groups (SRT ~ 2 dB). The least significant effect of both training types was found in the third test condition, i.e. when participants were repeating sentences accompanied with non-matching tactile vibrations and the performance in this condition was also poorest after training. The results indicate that both types of training may remove some level of difficulty in sound perception, which might enable a more proper use of speech inputs delivered via vibrotactile stimulation. We discuss the implications of these novel findings with respect to basic science. In particular, we show that even in adulthood, i.e. long after the classical "critical periods" of development have passed, a new pairing between a certain computation (here, speech processing) and an atypical sensory modality (here, touch) can be established and trained, and that this process can be rapid and intuitive. We further present possible applications of our training program and the SSD for auditory rehabilitation in patients with hearing (and sight) deficits, as well as healthy individuals in suboptimal acoustic situations.

Inhaled nitric oxide for the treatment of COVID-19 and other viral pneumonias in adults

RATIONALE: There is a growing population at increased risk of viral pneumonia;over 50,000 people in the United States died from pneumonia in 2015. RSV, influenza, and other viruses are common causes of severe viral lower respiratory tract infection (LRTI), and COVID-19 pneumonia is associated with high mortality rates. With limited treatment options currently available, viral COVID-19 LRTI in particular represents a significant unmet medical need. Inhaled nitric oxide (iNO) is a highly promising treatment option, given its documented antimicrobial and anti-inflammatory effects as well as beneficial effects on pulmonary vasculature. In particular, the antiviral effect of iNO on SARS-CoV-2 has been attributed to covalent binding to SARS-CoV-2 protease. In multiple clinical trials and compassionate use cases, intermittent exposure to 150 - 250 ppm iNO was well tolerated, resulted in improved physical and lung function, reduced bacterial load in patients with cystic fibrosis , and shortened time to improvement of clinical signs and time to fit for discharge in patients with acute bronchiolitis. Based on these data, we have initiated a prospective, randomized, open label, multi-center pilot clinical trial to evaluate the safety and efficacy of iNO for the treatment of viral pneumonia in adult patients. METHODS: In the current study, subjects (ages 18-80) with COVID-19 (COVID group) or other acute viral pneumonias (Viral LRTI group) requiring inpatient hospitalization are being randomized 1:1 to be treated with intermittent inhalations of 150 ppm iNO, given for 40 minutes 4 times daily for up to 7 days in addition to standard supportive treatment (SST), or to receive SST alone. iNO is being delivered by the LungFitTM, an innovative portable device under development (Beyond Air, NY, USA) that generates NO from room air. Study endpoints include safety, ICU admission, O2 supplementation requirement, and time to resolution of fever. RESULTS: The study will be conducted in up to 10 centers in Israel. To date, 6 subjects have been enrolled (COVID group), three have been randomized to iNO + SST and three to SST alone. All treatments have been well tolerated. CONCLUSIONS: Based on current data demonstrating the antiviral and anti-inflammatory effects of NO, in addition to its complex beneficial effect on oxygenation, iNO delivered by the LungFit system has the potential to treat viral pneumonias including COVID-19, thereby providing therapy for this currently unmet medical need.