NO-COVID-19: Inhaled Nitric Oxide for Preventing Progression in COVID-19

• Sponsor: Tufts Medical Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT04388683
• Collaborator: Bellerophon (Industry)
• Enrollment: 10
• Location: 1
• Arms: 2
• Actual Duration (Months): 6.4
• Patients Per Site Per Month: 1.6

Study Details

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

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

2. Supplemental O2 ≤ 2 liters/min; OR room air O2 saturation ≤ 94%

3. Supplemental nasal O2 >2 and <= 5 liters/min

4. Supplemental nasal O2 >5 liters/min

5. HFNC or NIV with FiO2 > 50%

6. Intubation, ECMO, or need to intubate with "Do not intubate" order

7. 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
• Actual Enrollment: 10 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
• Actual Primary Completion Date: Nov 23, 2020
• Actual Study Completion Date: Nov 23, 2020

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. Number of Participants With Average Maximum Disease Severity Assessed Through 28 Days [28 days]

   The clinical disease severity was assessed pre-randomization as the worse of 2 scores measured 2 hours apart. Patients eligible for randomization were those with scores of 1 or 2 (below), and randomization was stratified according to score (1 or 2). Study drug began within 1 hour of randomization. Beginning on the day following randomization ("day 1"), we calculated clinical score, daily, as the average of 3 measurements taken within 2 hour windows centered at 6AM, 2PM, and 10PM.

Secondary Outcome Measures

1. Days to Maximum Clinical Disease Severity Score [28 days]

   The number of days for participants to reach their maximum clinical disease severity score. Severity score assessed by the following table Stage Oxygen support 0 Not receiving O2 supplementation; AND room air O2 saturation ≥95% Supplemental O2 ≤ 2 liters/min; OR room air O2 saturation ≤ 94% Supplemental nasal O2 >2 and ≤ 5 liters/min Supplemental nasal O2 >5 liters/min HFNC or NIV with FiO2 > 50% Intubation, ECMO, or need to intubate with "Do not intubate" order Death

2. Days to Maximum Outcome Severity Score [28 days]

   The number of days for patients to reach maximum severity score from randomization. clinical score, daily, as the average of 3 measurements taken within 2 hour windows centered at 6AM, 2PM, and 10PM according to the following table: The following severity score 3 times daily, based on the level of oxygenation / ventilation support, where the treatment target is 92% ≤ O2 saturation < 96%: Stage Oxygen support 0 Not receiving O2 supplementation; AND room air O2 saturation ≥95% Supplemental O2 ≤ 2 liters/min; OR room air O2 saturation ≤ 94% Supplemental nasal O2 >2 and ≤ 5 liters/min Supplemental nasal O2 >5 liters/min HFNC or NIV with FiO2 > 50% Intubation, ECMO, or need to intubate with "Do not intubate" order Death HFNC = high-flow nasal cannula; NIV = non-invasive ventilation

3. Number of Participants in Each Stage at Maximum Severity [28 days]

   Maximum outcome severity score

4. Length of Hospital Stay [28 days]

   The numbers of days a patient spent in the hospital.

5. Mortality [28 days]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

4. positive nasal or oral pharyngeal swab by PCR, or

5. highly probable clinical picture based on clinical and CXR/CT scan

6. Requiring oxygen supplementation OR O2 saturation on room air of ≤ 94%

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

8. Age >= 60 years

9. T2DM or pre-diabetes as evidenced by either treatment with a hypoglycemic agent or any documented HgA1c >= 5.6

10. Obesity, based on BMI >= 30 kg/m2

11. 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

Locations

	Site	City	State	Country	Postal Code
1	Tufts Medical Center	Boston	Massachusetts	United States	02111

Sponsors and Collaborators

• Tufts Medical Center
• Bellerophon

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 27, 2020
• Informed Consent Form - Jul 24, 2020

More Information

Publications

None provided.

• Responsible Party: Tufts Medical Center
• ClinicalTrials.gov Identifier: NCT04388683
• Other Study ID Numbers: STUDY00000554
• First Posted: May 14, 2020
• Last Update Posted: Apr 19, 2022
• Last Verified: Apr 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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: COVID-19; Nitric Oxide

Study Results

Participant Flow

Pre-assignment Detail	Please note that 9 participants signed consent forms. However, only 8 participants completed the study because the last patient was consented the morning the study was shut down, so they did complete treatment steps or have data collected for them.

Arm/Group Title	Inhaled Nitric Oxide	Standard of Care
Arm/Group Description	Will receive study drug treatment. 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.	Will receive standard of care.
Period Title: Overall Study
STARTED	6	3
COMPLETED	5	3
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Intervention	Control	Total
Arm/Group Description	Will receive study drug treatment. 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.	Will receive standard of care.	Total of all reporting groups
Overall Participants	6	3	9
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	3 50%	3 100%	6 66.7%
>=65 years	3 50%	0 0%	3 33.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65 (14.2)	46.7 (1.5)	58.9 (14.5)
Sex: Female, Male (Count of Participants)
Female	2 33.3%	3 100%	5 55.6%
Male	4 66.7%	0 0%	4 44.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 33.3%	2 66.7%	4 44.4%
Not Hispanic or Latino	4 66.7%	1 33.3%	5 55.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 16.7%	1 33.3%	2 22.2%
White	5 83.3%	2 66.7%	7 77.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	6 100%	3 100%	9 100%
Clinical Disease Severity Score (Count of Participants)
Stage 1	5 83.3%	2 66.7%	7 77.8%
Stage 2	1 16.7%	1 33.3%	2 22.2%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Average Maximum Disease Severity Assessed Through 28 Days
Description	The clinical disease severity was assessed pre-randomization as the worse of 2 scores measured 2 hours apart. Patients eligible for randomization were those with scores of 1 or 2 (below), and randomization was stratified according to score (1 or 2). Study drug began within 1 hour of randomization. Beginning on the day following randomization ("day 1"), we calculated clinical score, daily, as the average of 3 measurements taken within 2 hour windows centered at 6AM, 2PM, and 10PM.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	Will receive study drug treatment. 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.	Will receive standard of care.
Measure Participants	5	3
Max. Clinical Disease Severity Score : Not receiving O2 Supp.; AND room air O2 saturation >95%	1 16.7%	1 33.3%
Max. Clinical Disease Severity Score : Supplemental O2 ≤2 liters/min; OR room air O2 saturation ≤94%	3 50%	1 33.3%
Max. Clinical Disease Severity Score : Supplemental nasal O2 >2 & ≤5 liters/min	1 16.7%	0 0%
Max. Clinical Disease Severity Score : HFNC or NIV with FiO2 >50%	0 0%	1 33.3%
HFNC or NIV with FiO2 >50%	0 0%	1 33.3%

2. Secondary Outcome

Title	Days to Maximum Clinical Disease Severity Score
Description	The number of days for participants to reach their maximum clinical disease severity score. Severity score assessed by the following table Stage Oxygen support 0 Not receiving O2 supplementation; AND room air O2 saturation ≥95% Supplemental O2 ≤ 2 liters/min; OR room air O2 saturation ≤ 94% Supplemental nasal O2 >2 and ≤ 5 liters/min Supplemental nasal O2 >5 liters/min HFNC or NIV with FiO2 > 50% Intubation, ECMO, or need to intubate with "Do not intubate" order Death
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	Will receive study drug treatment. 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.	Will receive standard of care.
Measure Participants	5	3
Median (Inter-Quartile Range) [Days]	1.0	1

3. Secondary Outcome

Title	Days to Maximum Outcome Severity Score
Description	The number of days for patients to reach maximum severity score from randomization. clinical score, daily, as the average of 3 measurements taken within 2 hour windows centered at 6AM, 2PM, and 10PM according to the following table: The following severity score 3 times daily, based on the level of oxygenation / ventilation support, where the treatment target is 92% ≤ O2 saturation < 96%: Stage Oxygen support 0 Not receiving O2 supplementation; AND room air O2 saturation ≥95% Supplemental O2 ≤ 2 liters/min; OR room air O2 saturation ≤ 94% Supplemental nasal O2 >2 and ≤ 5 liters/min Supplemental nasal O2 >5 liters/min HFNC or NIV with FiO2 > 50% Intubation, ECMO, or need to intubate with "Do not intubate" order Death HFNC = high-flow nasal cannula; NIV = non-invasive ventilation
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	Will receive study drug treatment. 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.	Will receive standard of care.
Measure Participants	5	3
Median (Inter-Quartile Range) [Days]	2.0	2.0

4. Secondary Outcome

Title	Number of Participants in Each Stage at Maximum Severity
Description	Maximum outcome severity score
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	Will receive study drug treatment. 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.	Will receive standard of care.
Measure Participants	5	3
Hospitalized, requiring supp. O2	1 16.7%	1 33.3%
Hospitalized, not requiring supp. O2 or ongoing medical care	3 50%	2 66.7%
Not hospitalized, no limitations on activities	1 16.7%	0 0%

5. Secondary Outcome

Title	Length of Hospital Stay
Description	The numbers of days a patient spent in the hospital.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	Will receive study drug treatment. 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.	Will receive standard of care.
Measure Participants	5	3
Median (Inter-Quartile Range) [Days]	3.0	3.0

6. Secondary Outcome

Title	Mortality
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	Will receive study drug treatment. 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.	Will receive standard of care.
Measure Participants	5	3
Count of Participants [Participants]	0 0%	0 0%

Adverse Events

Time Frame	The adverse events were monitored for up to 28 days after randomization.
Arm/Group Title	Intervention		Control
Arm/Group Description	Will receive study drug treatment. 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.		Will receive standard of care.
All Cause Mortality
	Intervention		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/3 (0%)
Serious Adverse Events
	Intervention		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/3 (0%)
Other (Not Including Serious) Adverse Events
	Intervention		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/3 (0%)

Limitations/Caveats

The study was terminated early by request of the company providing the iNO Drug. Our data set is small are analysis was effected by this.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.