Inhaled Nitric Oxide for Preventing Progression in COVID-19 (NO-COVID-19)

• ClinicalTrials.gov Identifier: NCT04388683
• Recruitment Status: Recruiting
• First Posted: May 14, 2020
• Last Update Posted: May 18, 2020
• Sponsor: Tufts Medical Center
• Collaborator: Bellerophon
• Information provided by (Responsible Party): Tufts Medical Center

Study Description

Brief Summary:

This is a pilot randomized-controlled (2:1) open label investigation of inhaled NO to prevent progression to more advanced disease in 42 hospitalized patients with COVID-19, at risk for worsening, based on baseline systemic oxygenation and 2 or more of the major risk factors of age > 60 years, type II DM, hypertension, and obesity.

Condition or disease	Intervention/treatment	Phase
COVID-19	Drug: Nitric Oxide	Phase 2

Detailed Description:

Primary Objective:

• To investigate the hypothesis that inhaled NO will reduce clinical worsening of hospitalized, high-risk patients with early COVID-19 to progressive systemic de-oxygenation, intubation, or death.

Secondary Objectives:

• To investigate the hypothesis that the beneficial effects of inhaled NO occur coincident with a decrease in systemic inflammation in COVID-19.

This is a pilot randomized-controlled (2:1) open label investigation of inhaled NO to prevent progression to more advanced disease in 42 hospitalized patients with COVID-19, at risk for worsening, based on baseline systemic oxygenation and 2 or more of the major risk factors of age > 60 years, type II DM, hypertension, and obesity.

We will perform computerized block randomization (on day zero) with a 2:1 study drug-to-control ratio to receive either open label pulsed inhaled nitric oxide, in addition to standard of care, or standard of care alone. Randomization will be stratified by being in clinical severity stage 1 or stage 2. Randomization will occur in blocks of 6 subjects: 4 iNO and 2 standard of care. Subjects will receive iNO using the INO pulse device at a dose of 125 mcg/kg IBW/hr (equivalent to approximately 20 ppm)

The clinical disease severity will be assessed pre-randomization as the worse of 2 scores measured 2 hours apart. Patients eligible for randomization will be those with scores of 1 or 2 (below), and randomization will be stratified according to score (1 or 2). Study drug will begin within 1 hour of randomization. Beginning on the day following randomization ("day 1"), we will be calculate clinical score, daily, as the average of 3 assessments made within 2 hour windows.

The patient will be followed, and clinical stage determined daily, through discharge, death or 28 days post-randomization. Treatment will be given for up to 2 weeks unless patient deteriorates and requires escalation to high flow or intubation or improves and is no longer deemed to need therapy.

The following severity score 3 times daily, based on the level of oxygenation / ventilation support, where the treatment target is 92% <= O2 saturation < 96%

: Scale Title:7-Point Respiratory Severity Scale Scale Range: 0-6 Higher values = worse

Stage Oxygen support

0. Not receiving O2 supplementation; AND room air O2 saturation ≥95%

1. Supplemental O2 ≤ 2 liters/min; OR room air O2 saturation ≤ 94%
2. Supplemental nasal O2 >2 and <= 5 liters/min
3. Supplemental nasal O2 >5 liters/min
4. HFNC or NIV with FiO2 > 50%
5. Intubation, ECMO, or need to intubate with "Do not intubate" order
6. Death

Treatment effect will also be assessed, as a secondary endpoint, via an alternate severity scale, assigned daily from the data accrued, as above, through 14 days post-randomization or discharge.

Data from this pilot study will be used to plan future a larger randomized controlled outcome trial.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Prevention of COVID-19 Progression Through Early Administration of Inhaled Nitric Oxide.
• Actual Study Start Date: May 12, 2020
• Estimated Primary Completion Date: April 30, 2021
• Estimated Study Completion Date: July 31, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Intervention; Will receive study drug treatment.	Drug: Nitric Oxide; Subjects will receive iNO using the INO pulse device at a dose of 125 mcg/kg IBW/hr (equivalent to approximately 20 ppm). The clinical disease severity will be assessed pre-randomization as the worse of 2 scores measured 2 hours apart. Patients eligible for randomization will be those with scores of 1 or 2 (below), and randomization will be stratified according to score (1 or 2). Study drug will begin within 1 hour of randomization. Beginning on the day following randomization ("day 1"), we will be calculate clinical score, daily, as the average of 3 measurements taken within 2 hour windows centered at 6AM, 2PM, and 10PM.
No Intervention: Control; Will receive standard of care.

Outcome Measures

Primary Outcome Measures :

1. Prevention of progressive systemic de-oxygenation, with escalation to higher levels of oxygen and ventilatory support or death, assessed using a 7-point severity scale. [ Time Frame: 28 days ]
   Prevention of progressive systemic de-oxygenation, with escalation to higher levels of oxygen and ventilatory support or death, assessed using a 7-point severity scale (See statistical methods). Between-group differences in the average maximum disease severity assessed through 28 days, through the following severity scores: a) increased liter oxygen flow, through a high flow nasal cannula; b) non-invasive ventilation; c) intubation or institution of ECMO; or d) death.

Secondary Outcome Measures :

1. Prevention of progression assessed by an alternate severity scale [ Time Frame: 28 days ]
2. Time to reaching maximal severity score [ Time Frame: 28 days ]
3. Proportion of patients in each stage at maximum severity [ Time Frame: 28 days ]
4. PaO2/FIO2 or SaO2/FIO2 ratio, measured daily [ Time Frame: 28 days ]
5. Length of hospital Stay (death assigned as worst case) [ Time Frame: 28 days ]
6. Frequency of Intubation, ECMO, or need to intubate with "Do Not Resuscitate" order [ Time Frame: 28 days ]
7. Mortality [ Time Frame: 28 days ]
8. IL6 level [ Time Frame: 7 days ]
9. TNF-alpha level [ Time Frame: 7 days ]
10. Fibrinogen level [ Time Frame: 7 days ]
11. CRP level [ Time Frame: 7 days ]
12. Ferritin Level [ Time Frame: 7 days ]
13. D-dimer level [ Time Frame: 7 days ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age 18-85 years.
2. Admitted to the hospital (med-surg or critical care) with dyspnea

3. Diagnosis of COVID-19 based on either

   1. positive nasal or oral pharyngeal swab by PCR, or
   2. highly probable clinical picture based on clinical and CXR/CT scan
4. Requiring oxygen supplementation OR O2 saturation on room air of ≤ 94%

5. At least 2 of the following 4 risk factors for clinical worsening:

   1. Age >= 60 years
   2. T2DM or pre-diabetes as evidenced by either treatment with a hypoglycemic agent or any documented HgA1c >= 5.6
   3. Obesity, based on BMI >= 30 kg/m2
   4. Hypertension, based on treatment with an antihypertensive medication or systolic or diastolic blood pressure measurement >= 140 or >= 90 mmHg, documented at enrollment or at any time within the prior 6 months.

Exclusion Criteria:

1. Intubated or prior intubation (during present hospitalization) or anticipated intubation within the subsequent 2 hours.
2. Receiving > 5L/min flow nasal O2 to maintain O2sat greater than or equal to 92%
3. Using high-flow nasal cannula (HFNC) or non-invasive ventilation (NIV)
4. Receiving iNO, a PDE5 inhibitor, oral or intravenous nitrates, nitroprusside, prilocaine, sulfonamides, or riociguat.
5. Other major pulmonary, cardiac, such as chronic obstructive lung disease or heart failure, or systemic illness or disease involvement with potential to represent the primary driver for clinical deterioration within the next 3 days.
6. History of group 1 pulmonary hypertension.
7. Pregnancy
8. Active breast feeding
9. Severe chronic kidney disease, either receiving renal replacement therapy or eGFR < 15 ml/min/m2
10. Acute kidney injury (AKI), evidenced by acute doubling of serum creatinine within previous 48 hours.
11. Clinically relevant spontaneous alteration of mental state
12. Inability to provide written informed consent.

Contacts and Locations

Contacts

Contact: Marvin Konstam, MD; 617-636-6293; mkonstam@tuftsmedicalcenter.org

Contact: Nicholas Hill, MD; 617-636-4288; nhill@tuftsmedicalcenter.org

Locations

United States, Massachusetts

Tufts Medical Center; Recruiting

Boston, Massachusetts, United States, 02111

Contact: Marvin Konstam, MD 617-636-6293 mkonstam@tuftsmedicalcenter.org

Sponsors and Collaborators

Tufts Medical Center

Bellerophon

Investigators

• Principal Investigator: Marvin Konstam, MD; Tufts Medical Center

More Information

• Responsible Party: Tufts Medical Center
• ClinicalTrials.gov Identifier: NCT04388683
• Other Study ID Numbers: STUDY00000554
• First Posted: May 14, 2020
• Last Update Posted: May 18, 2020
• Last Verified: May 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Data from this pilot study will be used to plan future a larger randomized controlled outcome trial.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Tufts Medical Center:

COVID-19; Inhaled Nitric Oxide

Additional relevant MeSH terms:

Respiratory Aspiration; Pathologic Processes; Respiration Disorders; Respiratory Tract Diseases; Nitric Oxide; Bronchodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Asthmatic Agents; Respiratory System Agents; Free Radical Scavengers; Antioxidants; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Endothelium-Dependent Relaxing Factors; Vasodilator Agents; Gasotransmitters; Protective Agents