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S-Nitrosylation Therapy of COVID-19

Primary Purpose

SARS-CoV2 Infection, Covid19

Status

Active

Phase

Early Phase 1

Locations

United States

Study Type

Interventional

Intervention

SNO

Nitrogen gas

About this trial

This is an interventional treatment trial for SARS-CoV2 Infection focused on measuring respiratory distress, respiratory failure

Eligibility Criteria

18 Years - 89 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

University Hospitals Cleveland Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

SNO

Placebo

Arm Description

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).

12 patients in the placebo arm will receive nitrogen gas (six-hour treatment).

Outcomes

Primary Outcome Measures

Treatment Emergent Adverse Events

Adverse events related to SNO therapy.

Frequency of Intubation

Number of intubations required.

Progression to use of ECMO

Use of ECMO required.

Secondary Outcome Measures

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

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

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

Duration of Hospitalization

Duration of total hospitalization days as measured by total hospitalization, ventilator and ICU days

All-Cause Mortality

All-cause mortality

Time to Discontinuation of Oxygen Therapy

Number of days required to discontinue oxygen supportive therapy

Discontinuation of Oxygen Therapy

Proportion of patients alive and with discontinued oxygen supportive therapy at day 30

Full Information

NCT ID

NCT04528771

First Posted

August 25, 2020

Last Updated

May 1, 2023

Sponsor

James Reynolds

Collaborators

Case Western Reserve University

1. Study Identification

Unique Protocol Identification Number

NCT04528771

Brief Title

S-Nitrosylation Therapy of COVID-19

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

August 5, 2021 (Actual)

Primary Completion Date

March 31, 2025 (Anticipated)

Study Completion Date

April 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

James Reynolds

Collaborators

Case Western Reserve University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

SARS-CoV2 Infection, Covid19

Keywords

respiratory distress, respiratory failure

7. Study Design

Primary Purpose

Treatment

Study Phase

Early Phase 1

Interventional Study Model

Parallel Assignment

Model Description

Single-site, double-blinded, randomized, placebo controlled trial with a superiority design. The study will randomize 24 patients 1:1 (12 treatment vs 12 control) to either S-nitrosylation therapy or placebo arms.

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

The investigational product will be prepared and dispensed by designated unblinded site personnel at the pharmacy; the investigational product label will indicate the study number but will not indicate the treatment assignment. Any site personnel involved in the administration and assessment of the investigational product will be blinded to subject treatment assignments throughout the study.

Allocation

Randomized

Enrollment

24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

SNO

Arm Type

Experimental

Arm Description

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).

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

12 patients in the placebo arm will receive nitrogen gas (six-hour treatment).

Intervention Type

Drug

Intervention Name(s)

SNO

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Nitrogen gas

Other Intervention Name(s)

Placebo

Intervention Description

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.

Primary Outcome Measure Information:

Title

Treatment Emergent Adverse Events

Description

Adverse events related to SNO therapy.

Time Frame

30 days

Title

Frequency of Intubation

Description

Number of intubations required.

Time Frame

30 days

Title

Progression to use of ECMO

Description

Use of ECMO required.

Time Frame

30 days

Secondary Outcome Measure Information:

Title

Time to Clinical Status Improvement

Description

Time Frame

30 days

Title

Clinical Status

Description

Time Frame

30 days

Title

Respiratory Clinical Status

Description

Time Frame

30 days

Title

Duration of Hospitalization

Description

Duration of total hospitalization days as measured by total hospitalization, ventilator and ICU days

Time Frame

30 days

Title

All-Cause Mortality

Description

All-cause mortality

Time Frame

30, 60 days

Title

Time to Discontinuation of Oxygen Therapy

Description

Number of days required to discontinue oxygen supportive therapy

Time Frame

30 days

Title

Discontinuation of Oxygen Therapy

Description

Proportion of patients alive and with discontinued oxygen supportive therapy at day 30

Time Frame

30 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

89 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Robert Schilz, DO, PhD

Organizational Affiliation

University Hospitals Cleveland Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

University Hospitals Cleveland Medical Center

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44106

Country

United States

12. IPD Sharing Statement

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S-Nitrosylation Therapy of COVID-19

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