S-Nitrosylation Therapy of COVID-19

Proof of Concept Safety Trial for S-Nitrosylation Therapy to Improve Oxygenation Status in Severe Covid-19 Patients Receiving Supplemental Oxygen Support

The primary objective of this study is to provide expanded access of S-nitrosylation therapy for the treatment of severe acute respiratory syndrome coronavirus (SARS-CoV2) infection.

Study Overview

• Status: Active, not recruiting
• Conditions: Covid19; SARS-CoV2 Infection
• Intervention / Treatment: Drug: SNO; Drug: Nitrogen gas

Detailed Description

Randomized controlled trial for safety of a 6-hour escalating dose of S-nitrosylation therapy or placebo to ventilated patients. This will be a single-site study conducted within the UH-CMC medical ICU designated COVID-19 quarantine areas.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 89 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria (Severe COVID-19 Status)

• Hospitalized with confirmed SARS-CoV-2 infection by polymerase chain reaction (PCR) or other validated tests as they become available within 30 days of enrollment.
• In mild respiratory distress, defined as a P/F ratio of between 200 and 325 mm Hg.
• Spontaneously breathing subjects receiving > 4 liters/min of oxygen.
• Patients enrolled and able to start ENO treatment after oxygen stabilization.
• Willing and able to provide written informed consent, or with a legal representative who can provide informed consent, or enrolled under International Conference on Harmonization (ICH) E6(R2) 4.8.15 emergency use provisions as deemed necessary by the investigator (participants ≥ 18 years of age).
• 18-89 years of age

Exclusion Criteria

• COVID-19 patients with mild to no respiratory distress, defined as P/F ratio > 325 mm Hg.
• COVID-19 patients receiving supplemental oxygen equivalent to an FiO2 of > 0.90 (reduction of FiO2 at this level or higher when ENO is blended into gas source cannot be avoided).
• COVID-19 patients receiving supplemental oxygen with active ventilatory support, CPAP, etc.
• Physician of record opposed to enrolling the patient due to perceived safety concerns; or any condition that does not allow the protocol to be followed safely.
• Subjects with past medical history of lung malignancy or pneumonectomy or lung transplant
• Subjects who have a history of malignancy or other irreversible disease/conditions with a 6-month mortality > 50%
• Subjects that have experienced cardiac arrest with CPR for longer than 30 minutes
• Patients on extracorporeal membrane oxygenation (ECMO) + patients intubated on ventilator
• Patient groups at an increased risk to form methemoglobin. (e.g. congenital variants of Met-Hb)
• Patients with anemia, defined as a hemoglobin of < 9 g/dL
• Individuals who are pregnant or breastfeeding
• Individuals with an acute disorder or history of chronic diseases of the heart, lungs, kidney, liver, or any other medical condition that in the opinion of the screening physician makes them unsuitable for study.
• Individuals taking nitrates.
• Individuals receiving PDE-5 inhibitors, any drugs that are nitric oxide donors (e.g. prilocaine, sodium nitroprusside and nitroglycerine), drugs known to increase methemoglobin (e.g. lidocaine, prilocaine, benzocaine, or dapsone), drugs that interfere with nitrite metabolism (e.g. allopurinol) and drugs that may potentiate hypotension (e.g. antihypertensives, diuretics, meperidine).
• Individuals with an inherited or acquired blood coagulation disorder, congenital methemoglobinemia, or a familial hemoglobinopathy that impacts oxygen delivery (e.g. sickle cell).
• Individuals who might have difficulty with the placement of a face mask (e.g. claustrophobia, uncontrolled asthma, severe allergies, sensitive skin) and/or the inhalation of a product for approximately 6 hours.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SNO; 12 patients in the S-nitrosylation arm will receive SNO (six-hour treatment with a sequential increasing dose regimen of 20 ppm x 2 hr, 40 ppm x 2 hr, 80 ppm x 2 hr).	Drug: SNO; Six-hour SNO treatment by inhalation at a sequential increasing dose regimen of 20 ppm x 2 hr, 40 ppm x 2 hr, 80 ppm x 2 hr. Patient care and follow-up during and after ENO administration will follow the critical care clinical SOPs developed by our institution (attached in Additional Information), which are consistent with the guidelines set out by the World Health Organization.
Placebo Comparator: Placebo; 12 patients in the placebo arm will receive nitrogen gas (six-hour treatment).	Drug: Nitrogen gas; Six-hour nitrogen gas treatment by inhalation.Patient care and follow-up during and after ENO administration will follow the critical care clinical SOPs developed by our institution (attached in Additional Information), which are consistent with the guidelines set out by the World Health Organization.; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Emergent Adverse Events	Adverse events related to SNO therapy.	30 days
Frequency of Intubation	Number of intubations required.	30 days
Progression to use of ECMO	Use of ECMO required.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Clinical Status Improvement	Number of days required to see a greater than or equal to 2 point improvement on the WHO 9-point clinical status assessment ordinal scale. Clinical status will be assessed using the WHO 9-point ordinal scale as follows: 0. Uninfected - no clinical or virological evidence of infection; Ambulatory - no limitation of activities; Ambulatory - Limitation of activities; Hospitalized, mild disease - no oxygen therapy; Hospitalized, mild disease - oxygen by mask or nasal prongs; Hospitalized, severe disease - non-invasive ventilation or high-flow oxygen; Hospitalized, severe disease - intubation and mechanical ventilation; Hospitalized, severe disease - ventilation + additional organ support (pressors, RRT, ECMO); Dead	30 days
Clinical Status	Proportion of patients in each stage at maximum severity on the 9-point clinical status assessment ordinal scale. Clinical status will be assessed using the WHO 9-point ordinal scale as follows: 0. Uninfected - no clinical or virological evidence of infection; Ambulatory - no limitation of activities; Ambulatory - Limitation of activities; Hospitalized, mild disease - no oxygen therapy; Hospitalized, mild disease - oxygen by mask or nasal prongs; Hospitalized, severe disease - non-invasive ventilation or high-flow oxygen; Hospitalized, severe disease - intubation and mechanical ventilation; Hospitalized, severe disease - ventilation + additional organ support (pressors, RRT, ECMO); Dead	30 days
Respiratory Clinical Status	Respiratory clinical status assessed by a 7-point respiratory status ordinal scale that captures oxygen requirement, ventilator support or death. 7-Point Respiratory Severity Scale Range: 1-7 Higher values = worse; Not receiving oxygen supplementation; AND room air oxygen saturation ≥ 95%; Supplemental oxygen ≤ 2 liters/min; OR room air oxygen saturation ≤ 94%; Supplemental nasal oxygen >2 and <= 5 liters/min; Supplemental nasal oxygen >5 liters/min; HFNC or NIV with FiO2 > 50%; Intubation or ECMO; Death	30 days
Duration of Hospitalization	Duration of total hospitalization days as measured by total hospitalization, ventilator and ICU days	30 days
All-Cause Mortality	All-cause mortality	30, 60 days
Time to Discontinuation of Oxygen Therapy	Number of days required to discontinue oxygen supportive therapy	30 days
Discontinuation of Oxygen Therapy	Proportion of patients alive and with discontinued oxygen supportive therapy at day 30	30 days

Collaborators and Investigators

• Sponsor: James Reynolds
• Collaborators: Case Western Reserve University
• Investigators: Principal Investigator: Robert Schilz, DO, PhD, University Hospitals Cleveland Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): August 5, 2021
• Primary Completion (Anticipated): March 31, 2025
• Study Completion (Anticipated): April 30, 2025

Study Registration Dates

• First Submitted: August 25, 2020
• First Submitted That Met QC Criteria: August 25, 2020
• First Posted (Actual): August 27, 2020

Study Record Updates

• Last Update Posted (Actual): May 3, 2023
• Last Update Submitted That Met QC Criteria: May 1, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: respiratory distress; respiratory failure
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: STUDY20210599

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No