Inhaled Nitric Oxide for Preventing Progression in COVID-19

NCT ID: NCT04388683

Last Updated: 2022-04-19

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-05-12
• Study Completion Date: 2020-11-23

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.

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.

Conditions

COVID-19

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Intervention

Will receive study drug treatment.

Group Type: EXPERIMENTAL

Nitric Oxide

Intervention Type: DRUG

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.

Control

Will receive standard of care.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

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.

Intervention Type: DRUG

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bellerophon

INDUSTRY

Sponsor Role: collaborator

Tufts Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marvin Konstam, MD

Role: PRINCIPAL_INVESTIGATOR

Tufts Medical Center

Locations

Tufts Medical Center

Boston, Massachusetts, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

STUDY00000554

Identifier Type: -

Identifier Source: org_study_id