Coronavirus, Coronavirus Infection, COVID-19
Conditions
Keywords
COVID, Sars-CoV-2, iNO, INOpulse, Severe Acute Respiratory Syndrome (SARS) Pneumonia, Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV 2, COViNOX, pulsed inhaled nitric oxide, inhaled nitric oxide, portable pulsed inhaled nitric oxide, nitric oxide
Brief summary
A randomized, double-blind, placebo-controlled study to assess the efficacy and safety of pulsed inhaled iNO compared to placebo in subjects with COVID-19.
Detailed description
This is a randomized, double-blind, placebo-controlled study to assess the efficacy and safety of pulsed iNO compared to placebo in subjects with COVID-19 who are hospitalized and require supplemental oxygen without assisted ventilation. Subjects will be randomized to receive placebo or iNO125 mcg/kg ideal body weight (IBW)/hour 24 hours daily up to 14 days or until resolution or discharge.
Interventions
COMBINATION_PRODUCTINOpulse
Subjects will be treated by means of an INOpulse device using an INOpulse nasal cannula.
COMBINATION_PRODUCTPlacebo
Subjects will be treated by means of an INOpulse device using an INOpulse nasal cannula.
Sponsors
Bellerophon Pulse Technologies
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent * At least 18 years old * Subjects must be hospitalized and have the following: * proven or high suspicion of SARS-CoV-2 infection and, * requiring oxygen supplementation defined as: * SpO2 ≤ 92% regardless of supplemental oxygen (ie on room air or on oxygen), or * SpO2 ≥ 92% on supplemental O2 and in the opinion of the Investigator it is not safe to decrease or remove the supplemental oxygen * require supplemental oxygen of no more than 10 L/minute, and * radiologic suspected or proven COVID-19 pneumonitis (chest x-ray or CT scan) * Female subjects must have a negative pregnancy test * Willing and able to comply with the treatment schedule and study procedures
Exclusion criteria
* Participating in another clinical trial of an investigational treatment for COVID-19 * Methemoglobin \> 3% * Evidence of severe multi organ failure * Use of assisted ventilation prior to initiation of iNO * Pregnancy or positive pregnancy test pre-dose * Open tracheostomy * Chronic use of a nitric oxide donor agent such as nitroglycerin or drugs known to increase methemoglobin such as lidocaine, prilocaine, benzocaine, nitroprusside, isosorbide, or dapsone at screening * History or clinical evidence of systolic heart failure, left ventricular dysfunction (LVEF \<40%) * Subjects reporting massive hemoptysis associated with the current illness or with radiologically proven pulmonary embolus
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Subjects Who Died or Had Respiratory Failure | Through Day 28 | The number of subjects who died or had respiratory failure through Day 28 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects to Recover | Through Day 28 | Number of subjects to recover, where recover is defined as attaining a NIAID Ordinal score of 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen or 8) Not hospitalized, no limitations on activities sustained through Day 28, or discharge from hospital without re admission for COVID. |
| Clinical Status Using National Institute of Allergy and Infectious Diseases (NIAID) 8-point Ordinal Scale | Day 7 | The assessment of clinical status at the first assessment of a study day. The scale is: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring 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, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities. |
| Number of Subjects Discharged Alive From Hospital | Through Day 28 | Number of subjects discharged alive from hospital through Day 28 |
| All Cause Mortality | Through Day 28 | All cause mortality through Day 28 |
| Difference in Proportion in RT-PCR Results at Discharge by Treatment Group | Through Day 28 | Proportion of subjects with a positive RT-PCR result at baseline from a nasopharyngeal swab through Day 28 reported as a proportion of positive or negative RT-PCR testing. |
| Duration of Hospitalization | Through Day 28 | Duration of Hospitalization through Day 28 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Adverse Events Leading to Study Drug Discontinuation | Through Day 28 | Number of subjects with adverse events leading to study drug discontinuation through Day 28 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Inhaled Nitric Oxide (iNO) Pulsed inhaled iNO 125 mcg/kg IBW/hour
INOpulse: Subjects will be treated by means of an INOpulse device using an INOpulse nasal cannula. | 95 |
| Placebo Pulsed inhaled N2, 99.999% gas
Placebo: Subjects will be treated by means of an INOpulse device using an INOpulse nasal cannula. | 96 |
| Total | 191 |
Baseline characteristics
| Characteristic | Inhaled Nitric Oxide (iNO) | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 33 Participants | 36 Participants | 69 Participants |
| Age, Categorical Between 18 and 65 years | 62 Participants | 59 Participants | 121 Participants |
| Age, Continuous | 58.0 years STANDARD_DEVIATION 14.96 | 59.1 years STANDARD_DEVIATION 13.72 | 58.6 years STANDARD_DEVIATION 14.33 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 28 Participants | 32 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 66 Participants | 64 Participants | 130 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized America Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Black or African American | 11 Participants | 17 Participants | 28 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 10 Participants | 9 Participants | 19 Participants |
| Race/Ethnicity, Customized White | 68 Participants | 68 Participants | 136 Participants |
| Region of Enrollment United States | 95 participants | 96 participants | 191 participants |
| Sex: Female, Male Female | 48 Participants | 44 Participants | 92 Participants |
| Sex: Female, Male Male | 47 Participants | 52 Participants | 99 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 91 | 1 / 95 |
| other Total, other adverse events | 16 / 91 | 28 / 95 |
| serious Total, serious adverse events | 13 / 91 | 12 / 95 |
Outcome results
Primary
The Number of Subjects Who Died or Had Respiratory Failure
The number of subjects who died or had respiratory failure through Day 28
Time frame: Through Day 28
Population: All Randomized Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inhaled Nitric Oxide (iNO) | The Number of Subjects Who Died or Had Respiratory Failure | 12 Participants |
| Placebo | The Number of Subjects Who Died or Had Respiratory Failure | 10 Participants |
p-value: 0.6316Regression, Logistic
p-value: 0.412795% CI: [0.567, 3.977]Regression, Logistic
Secondary
All Cause Mortality
All cause mortality through Day 28
Time frame: Through Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inhaled Nitric Oxide (iNO) | All Cause Mortality | 5 Participants |
| Placebo | All Cause Mortality | 1 Participants |
Secondary
Clinical Status Using National Institute of Allergy and Infectious Diseases (NIAID) 8-point Ordinal Scale
The assessment of clinical status at the first assessment of a study day. The scale is: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring 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, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.
Time frame: Day 28
Population: All Randomized Analysis Set with NIAID scores at Day 28
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Nitric Oxide (iNO) | Clinical Status Using National Institute of Allergy and Infectious Diseases (NIAID) 8-point Ordinal Scale | 6.56 score on a scale | Standard Error 0.193 |
| Placebo | Clinical Status Using National Institute of Allergy and Infectious Diseases (NIAID) 8-point Ordinal Scale | 6.87 score on a scale | Standard Error 0.186 |
Secondary
Clinical Status Using National Institute of Allergy and Infectious Diseases (NIAID) 8-point Ordinal Scale
The assessment of clinical status at the first assessment of a study day. The scale is: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring 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, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.
Time frame: Day 14
Population: All Randomized Analysis Set with NIAID scores at Day 14
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Nitric Oxide (iNO) | Clinical Status Using National Institute of Allergy and Infectious Diseases (NIAID) 8-point Ordinal Scale | 6.22 score on a scale | Standard Error 0.208 |
| Placebo | Clinical Status Using National Institute of Allergy and Infectious Diseases (NIAID) 8-point Ordinal Scale | 6.38 score on a scale | Standard Error 0.202 |
Secondary
Clinical Status Using National Institute of Allergy and Infectious Diseases (NIAID) 8-point Ordinal Scale
The assessment of clinical status at the first assessment of a study day. The scale is: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring 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, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.
Time frame: Day 7
Population: All Randomized Analysis Set with NIAID scores at Day 7
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Nitric Oxide (iNO) | Clinical Status Using National Institute of Allergy and Infectious Diseases (NIAID) 8-point Ordinal Scale | 5.28 score on a scale | Standard Error 0.198 |
| Placebo | Clinical Status Using National Institute of Allergy and Infectious Diseases (NIAID) 8-point Ordinal Scale | 5.81 score on a scale | Standard Error 0.192 |
Secondary
Difference in Proportion in RT-PCR Results at Discharge by Treatment Group
Proportion of subjects with a positive RT-PCR result at baseline from a nasopharyngeal swab through Day 28 reported as a proportion of positive or negative RT-PCR testing.
Time frame: Through Day 28
Population: Difference in converted RT-PCR Results at Discharge by Treatment Group. Only participants with a positive RT-PCR result at baseline are included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Inhaled Nitric Oxide (iNO) | Difference in Proportion in RT-PCR Results at Discharge by Treatment Group | Positive RT-PCR Result | 0.841 Proportion Converted |
| Inhaled Nitric Oxide (iNO) | Difference in Proportion in RT-PCR Results at Discharge by Treatment Group | Negative RT-PCR Result | 0.159 Proportion Converted |
| Placebo | Difference in Proportion in RT-PCR Results at Discharge by Treatment Group | Positive RT-PCR Result | 0.812 Proportion Converted |
| Placebo | Difference in Proportion in RT-PCR Results at Discharge by Treatment Group | Negative RT-PCR Result | 0.188 Proportion Converted |
p-value: 0.6635Chi-squared
Secondary
Duration of Hospitalization
Duration of Hospitalization through Day 28
Time frame: Through Day 28
Population: (1) Subject hospital duration will be defined as the time from Day 1 (start of study treatment) to the day of hospital discharge or Day 28 of treatment for patients who are still hospitalized. If a patient has expired on or before Day 27 of treatment, they will be assigned a value of 28 days. (2) For patients who were randomized but not treated, the date of randomization is used in place of the treatment start date.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Nitric Oxide (iNO) | Duration of Hospitalization | 8.9 Days | Standard Deviation 6.58 |
| Placebo | Duration of Hospitalization | 8.1 Days | Standard Deviation 6.36 |
Secondary
Number of Subjects Discharged Alive From Hospital
Number of subjects discharged alive from hospital through Day 28
Time frame: Through Day 28
Population: (1) Discharged is defined as discharged alive from hospital through day 28. (2) For patients who were randomized but not treated, the date of randomization is used in place of the treatment start date.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Inhaled Nitric Oxide (iNO) | Number of Subjects Discharged Alive From Hospital | Discharged | 89 Participants |
| Inhaled Nitric Oxide (iNO) | Number of Subjects Discharged Alive From Hospital | Not Discharged | 6 Participants |
| Inhaled Nitric Oxide (iNO) | Number of Subjects Discharged Alive From Hospital | Missing Data | 0 Participants |
| Placebo | Number of Subjects Discharged Alive From Hospital | Discharged | 88 Participants |
| Placebo | Number of Subjects Discharged Alive From Hospital | Not Discharged | 7 Participants |
| Placebo | Number of Subjects Discharged Alive From Hospital | Missing Data | 1 Participants |
Secondary
Number of Subjects to Recover
Number of subjects to recover, where recover is defined as attaining a NIAID Ordinal score of 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen or 8) Not hospitalized, no limitations on activities sustained through Day 28, or discharge from hospital without re admission for COVID.
Time frame: Through Day 28
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Inhaled Nitric Oxide (iNO) | Number of Subjects to Recover | Recovered | 61 Participants |
| Inhaled Nitric Oxide (iNO) | Number of Subjects to Recover | Not Recovered | 34 Participants |
| Placebo | Number of Subjects to Recover | Not Recovered | 26 Participants |
| Placebo | Number of Subjects to Recover | Recovered | 70 Participants |
Other Pre-specified
Number of Subjects With Adverse Events Leading to Study Drug Discontinuation
Number of subjects with adverse events leading to study drug discontinuation through Day 28
Time frame: Through Day 28
Population: Full Safety Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inhaled Nitric Oxide (iNO) | Number of Subjects With Adverse Events Leading to Study Drug Discontinuation | 11 Participants |
| Placebo | Number of Subjects With Adverse Events Leading to Study Drug Discontinuation | 11 Participants |