A Study to Assess Efficacy and Safety of RESP301 Plus Standard of Care (SOC) Compared to SOC Alone in Hospitalized Participants With COVID-19

Study Overview
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Brief Summary
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The effect of RESP301 as an add on treatment to SOC will be evaluated for its efficacy in reducing rate of progression to a more severe level of COVID-19 and for safety, by comparison with SOC alone in hospitalized COVID-19 patients.

Detailed Description
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This is an open-label, randomized, multicenter, parallel group, concurrent, controlled study using a sequential adaptive design to evaluate the efficacy and safety of RESP301 plus SOC versus SOC alone in hospitalized patients with COVID-19 (World Health Organization [WHO] ordinal scale level 3 or 4). Approximately 300 participants will be enrolled and randomized 2:1 to the Investigational arm or the Control arm. The study will be divided into the following periods: Screening period: (up to 2 days), Intervention (up to 10 days), follow-up (Day 14 and Day 28).

Official Title
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An Open-label, Adaptive Randomized, Controlled Multicenter Study to Evaluate the Efficacy and Safety of RESP301 Plus Standard of Care (SOC) Compared to SOC Alone in Hospitalized Participants With COVID-19 WHO Grade 3&4 (NOCoV2)

Conditions
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COVID-19

Intervention / Treatment
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* Drug: RESP301, a Nitric Oxide generating solution
* Other: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has laboratory-confirmed SARS-CoV-2 infection as determined by reverse transcriptase polymerase chain reaction (RT-PCR) or other approved clinical testing prior to randomization. Participant is hospitalized in relation to COVID-19, requiring supplemental oxygen to maintain SpO2 at a safe level (WHO level 3 & 4). Participant is capable of giving signed informed consent Participant is male or female. All females of childbearing potential, including pregnant females, must consent to urine pregnancy testing at screening to be eligible for the study. Exclusion Criteria: Rapidly deteriorating or likely to require escalation to high flow oxygen, invasive or non-invasive ventilatory support within 24 hours according to Investigator's opinion. Unable to safely receive a nebulized treatment for approximately 8 minutes according to Investigator's opinion. Unable to receive or considered ineligible for invasive or non-invasive ventilatory support. History of methemoglobinemia. Presence of uncontrolled asthma, history of severe bronchospasm. Presence of severe chronic respiratory disease and tracheostomy. Suspected or confirmed untreated, active tuberculosis. Severely immune-compromised participants in Investigator's opinion. Recent active coronary artery disease or decompensated heart failure.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational arm<br>Participants will receive inhaled RESP301 administered using a nebulizer three times a day for up to 10 days in addition to the standard of care. | Drug: RESP301, a Nitric Oxide generating solution<br>* Product application requires inhalation using a standard handheld nebulizer.<br>Other: Standard of Care<br>* Participants will receive institutional SOC for the treatment of COVID-19.<br>|
| Active Comparator: Control arm<br>Participants will receive institutional SOC for the treatment of COVID-19 | Other: Standard of Care<br>* Participants will receive institutional SOC for the treatment of COVID-19.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Progress by at Least One Level Higher on the Modified WHO Ordinal Scale | A modified WHO ordinal scale was used for consistency with the recent study in adults hospitalized with severe COVID-19, to record the participant's status at the time of assessment. The modified WHO ordinal scale included the following levels : 1= Not hospitalized, no limitations on activities; 2= Not hospitalized, limitation on activities; 3= Hospitalized, not requiring supplemental oxygen; 4= Hospitalized, requiring supplemental oxygen; 5= Hospitalized, on non-invasive ventilation or high-flow oxygen devices; 6= Hospitalized, on invasive mechanical ventilation or extra corporeal membrane oxygenation (ECMO); 7= Death. Higher scores mean worse outcome. The number of participants that had an increase in at least one level higher score on the modified WHO ordinal scale was assessed. | Baseline, Day 2 and Day 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Room Air Oxygen Saturation (SpO2) From Baseline Over Time | Pulse oximetry measurements were performed to evaluate SpO2. The effect of RESP301 as measured by room air SpO2 was assessed. | Day 1 (Baseline) Post-Nebulization, Day 2, 3, 4, 5, 6, and 7 | 
| Change in National Early Warning Score (NEWS) 2 Symptom Score From Baseline Over Time | The NEWS is based on a simple aggregate scoring system in which a score is allocated to physiological measurements, already recorded in routine practice, when patients present to, or are being monitored in hospital. Six simple physiological parameters form the basis of the scoring system: 1. Respiration rate; 2. Oxygen saturation; 3. Systolic blood pressure; 4. Pulse rate; 5. Level of consciousness or new confusion; 6. Temperature. Each score is 0-3 and individual scores are added together for an overall score. An additional two points are added if the patient is receiving oxygen therapy. The total possible score ranges from 0 to 20. The higher the score the greater the clinical risk. Higher scores indicate the need for escalation, medical review and possible clinical intervention, and more intensive monitoring. | Day 1 (Baseline), Day 2, 3, 4, 5, 6, and 7 | 
| Change From Baseline for Number of Participants on the Modified WHO Ordinal Scale at Each Visit | A modified WHO ordinal scale was used for consistency with the recent study in adults hospitalized with severe COVID-19, to record the participant's status at the time of assessment. The modified WHO ordinal scale included the following levels : 1= Not hospitalized, no limitations on activities; 2= Not hospitalized, limitation on activities; 3= Hospitalized, not requiring supplemental oxygen; 4= Hospitalized, requiring supplemental oxygen; 5= Hospitalized, on non-invasive ventilation or high-flow oxygen devices; 6= Hospitalized, on invasive mechanical ventilation or extra corporeal membrane oxygenation (ECMO); 7= Death. Higher scores mean worse outcome. Change from baseline for Number of Participants on the modified WHO ordinal scale was assesed. | Day 1 (Baseline), Day 2, 3, 4, 5, 6, and 7 | 
| Time to Improvement of at Least One Level Lower on the Modified WHO Ordinal Scale | Time to improvement is the time in which the participant sees a decrease after first study treatment in the WHO 7-point ordinal scale from baseline to a value at least one level lower in days (date of decrease in WHO scale - first dose date + 1). In the case that a patient has not decreased in the WHO scale at time of analysis or withdraws from the study before leaving the hospital, they would be censored at their date of last assessment in the data cut or early discontinuation date, respectively. | From Baseline to Day 28 | 
| Time to Progression of at Least One Level Higher on the Modified WHO Ordinal Scale | Time to progression is the time in which the patient sees an increase after first study treatment in the WHO 7-point ordinal scale from baseline to a value at least one level higher in days (date of increase in WHO scale - first dose date + 1). In the case that a patient has not increased in the WHO scale at time of analysis or withdraws from the study before leaving the hospital, they would be censored at their date of last assessment in the data cut or early discontinuation date, respectively. | From Baseline to Day 28 | 
| Number of Participants With Adverse Events | AEs (non-serious) as variables of safety and tolerability of RESP301 were assessed. Severe AEs is defined as an event that prevents normal everyday activities. An AE that is assessed as severe should not be confused with an SAE. Severe is a category utilized for rating the intensity of an event; and both AE and SAE can be assessed as severe. | From screening to safety follow up (Day 28) | 
| Time to Hospital Discharge | Time to hospital discharge is the time in the hospital after first study treatment in days (date of discharge - first dose date + 1). Patients who die before leaving the hospital would be considered failures (did not achieve hospital discharge) and censored. In the case that a patient is still hospitalized at time of analysis or withdraws from the study before leaving the hospital, they would be censored at their date of last assessment in the data cut or early discontinuation date, respectively. | Day 10 | 
| Number of Participants With Mortality by Day 28 | Incidence of mortality by Day 28 is the number of participants who have died by Day 28 and the percentage of patients reaching this endpoint will be summarized by treatment group. | Day 28 | 
| Reduction in Oxygen Saturation (SpO2) to <90% | Room Air SpO2 for a summary of participants with reduction to < 90%, unless well clinically tolerated according to Investigator's opinion was assesed. | Day 1 (Baseline), Day 2, Day 3 | 
| Events of Clinical Bronchial Hyper Responsiveness Related to Nebulization | Incidence of clinical bronchial hyper responsiveness related to nebulization was assessed. Oxygen saturation decreased and wheezing was assessed as an incidence of clinical bronchial hyper-responsiveness related to nebulization, requiring temporal increase of supplemental oxygen. | From screening to safety follow up (Day 28) |