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S-Nitrosylation Therapy of COVID-19

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04528771
Recruitment Status : Active, not recruiting
First Posted : August 27, 2020
Last Update Posted : October 21, 2021
Sponsor:
Collaborator:
Case Western Reserve University
Information provided by (Responsible Party):
Robert Schilz, University Hospitals Cleveland Medical Center

Tracking Information
First Submitted Date  ICMJE August 25, 2020
First Posted Date  ICMJE August 27, 2020
Last Update Posted Date October 21, 2021
Actual Study Start Date  ICMJE August 5, 2021
Estimated Primary Completion Date March 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 13, 2021)
  • Treatment Emergent Adverse Events [ Time Frame: 30 days ]
    Adverse events related to SNO therapy.
  • Frequency of Intubation [ Time Frame: 30 days ]
    Number of intubations required.
  • Progression to use of ECMO [ Time Frame: 30 days ]
    Use of ECMO required.
Original Primary Outcome Measures  ICMJE
 (submitted: August 25, 2020)
  • Length of Hospital Stay [ Time Frame: 30 days ]
    Total hospitalization days: Hospitalization data will be collected from the EMR on Day 30. Treatment 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.
  • Number of Ventilator Days [ Time Frame: 30 days ]
    Total ventilator days:Ventilator Days will be recorded for each day through Day 30. The number of days on the ventilator will be counted and then used to calculate the number of ventilator free days. Days that subjects are weaning off and on the ventilator will be counted as days on the ventilator.
  • Length of Intensive Care [ Time Frame: 30 days ]
    Total days in ICU: Intensive Care Unit Days will be recorded for each day through Day 30. Days will be counted in 24-hour periods, any partial days will be counted as a whole day. The level of ICU care needed will be recorded, based on clear definitions and specific clinical criteria in the covid-19 critical care procedure manual, as follows:
    • Level 1 - Mechanical ventilation and intensivist support. Patient is stable on lung protective equipment.
    • Level 2 - Advanced mechanical ventilation (capability to prone) and 24 hour intensivist support. Patient is hypoxic. Patient is stabilized on escalated ventilator settings (high PEEP, prone, etc.)
    • Level 3 - Advanced oxygenation/ventilation strategies, including ECMO and 24 intensivist support. Patient is severely hypoxic (ARDS), code status is discussed, palliative consult is discussed, RESP-ECMO parameters, and patient is ECMO candidate.
  • All-Cause Mortality [ Time Frame: 30 days ]
    30-day all-cause mortality
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 13, 2021)
  • Time to Clinical Status Improvement [ Time Frame: 30 days ]
    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
    1. Ambulatory - no limitation of activities
    2. Ambulatory - Limitation of activities
    3. Hospitalized, mild disease - no oxygen therapy
    4. Hospitalized, mild disease - oxygen by mask or nasal prongs
    5. Hospitalized, severe disease - non-invasive ventilation or high-flow oxygen
    6. Hospitalized, severe disease - intubation and mechanical ventilation
    7. Hospitalized, severe disease - ventilation + additional organ support (pressors, RRT, ECMO)
    8. Dead
  • Clinical Status [ Time Frame: 30 days ]
    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
    1. Ambulatory - no limitation of activities
    2. Ambulatory - Limitation of activities
    3. Hospitalized, mild disease - no oxygen therapy
    4. Hospitalized, mild disease - oxygen by mask or nasal prongs
    5. Hospitalized, severe disease - non-invasive ventilation or high-flow oxygen
    6. Hospitalized, severe disease - intubation and mechanical ventilation
    7. Hospitalized, severe disease - ventilation + additional organ support (pressors, RRT, ECMO)
    8. Dead
  • Respiratory Clinical Status [ Time Frame: 30 days ]
    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
    1. Not receiving oxygen supplementation; AND room air oxygen saturation ≥ 95%
    2. Supplemental oxygen ≤ 2 liters/min; OR room air oxygen saturation ≤ 94%
    3. Supplemental nasal oxygen >2 and <= 5 liters/min
    4. Supplemental nasal oxygen >5 liters/min
    5. HFNC or NIV with FiO2 > 50%
    6. Intubation or ECMO
    7. Death
  • Duration of Hospitalization [ Time Frame: 30 days ]
    Duration of total hospitalization days as measured by total hospitalization, ventilator and ICU days
  • All-Cause Mortality [ Time Frame: 30, 60 days ]
    All-cause mortality
  • Time to Discontinuation of Oxygen Therapy [ Time Frame: 30 days ]
    Number of days required to discontinue oxygen supportive therapy
  • Discontinuation of Oxygen Therapy [ Time Frame: 30 days ]
    Proportion of patients alive and with discontinued oxygen supportive therapy at day 30
Original Secondary Outcome Measures  ICMJE
 (submitted: August 25, 2020)
  • Treatment Emergent Adverse Events [ Time Frame: 30 days ]
    Adverse events related to SNO therapy.
  • Time to Respiratory Status Improvement [ Time Frame: 30 days ]
    Number of days required to see a greater than 2 point improvement on a 7-point respiratory status assessment ordinal scale. 7-Point Respiratory Severity Scale Range: 1-7 Higher values = worse
    1. Not receiving oxygen supplementation; AND room air oxygen saturation ≥ 95%
    2. Supplemental oxygen ≤ 2 liters/min; OR room air oxygen saturation ≤ 94%
    3. Supplemental nasal oxygen >2 and <= 5 liters/min
    4. Supplemental nasal oxygen >5 liters/min
    5. HFNC or NIV with FiO2 > 50%
    6. Intubation or ECMO
    7. Death
  • Clinical Status [ Time Frame: 30 days ]
    Proportion of patients in each stage at maximum severity on the 7-point clinical status assessment ordinal scale. Clinical status will be assessed using a 7-point ordinal scale as follows:
    1. Death
    2. Hospitalized, on invasive mechanical ventilation or ECMO
    3. Hospitalized, on non-invasive ventilation or high flow oxygen devices
    4. Hospitalized, requiring low flow supplemental oxygen
    5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise)
    6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care
    7. Not hospitalized
  • Respiratory Clinical Status [ Time Frame: 30 days ]
    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
    1. Not receiving oxygen supplementation; AND room air oxygen saturation ≥ 95%
    2. Supplemental oxygen ≤ 2 liters/min; OR room air oxygen saturation ≤ 94%
    3. Supplemental nasal oxygen >2 and <= 5 liters/min
    4. Supplemental nasal oxygen >5 liters/min
    5. HFNC or NIV with FiO2 > 50%
    6. Intubation or ECMO
    7. Death
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE S-Nitrosylation Therapy of COVID-19
Official Title  ICMJE Proof of Concept Safety Trial for S-Nitrosylation Therapy to Improve Oxygenation Status in Severe Covid-19 Patients Receiving Supplemental Oxygen Support
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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: Quadruple (Participant, Care Provider, Investigator, Outcomes 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.
Primary Purpose: Treatment
Condition  ICMJE
  • SARS-CoV2 Infection
  • Covid19
Intervention  ICMJE
  • 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.
  • 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 Name: Placebo
Study Arms  ICMJE
  • 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).
    Intervention: Drug: SNO
  • Placebo Comparator: Placebo
    12 patients in the placebo arm will receive nitrogen gas (six-hour treatment).
    Intervention: Drug: Nitrogen gas
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: October 13, 2021)
24
Original Estimated Enrollment  ICMJE
 (submitted: August 25, 2020)
21
Estimated Study Completion Date  ICMJE April 30, 2022
Estimated Primary Completion Date March 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 89 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04528771
Other Study ID Numbers  ICMJE STUDY20210599
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Robert Schilz, University Hospitals Cleveland Medical Center
Study Sponsor  ICMJE Robert Schilz
Collaborators  ICMJE Case Western Reserve University
Investigators  ICMJE
Principal Investigator: Robert Schilz, DO, PhD University Hospitals Cleveland Medical Center
PRS Account University Hospitals Cleveland Medical Center
Verification Date October 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP