COVID-19
Conditions
Keywords
Acute Lung Injury, Hypoxia, Corona virus, COVID-19, SARS (Severe Acute Respiratory Syndrome), Acute Respiratory Distress Syndrome, ARDS
Brief summary
The study is a randomized controlled, open-label trial comparing subcutaneous Zilucoplan® with standard of care to standard of care alone. In the active group, Zilucoplan® will be administered subcutaneously once daily for 14 days or till discharge from the hospital, whichever comes first. The hypothesis of the proposed intervention is that Zilucoplan® (complement C5 inhibitor) has profound effects on inhibiting acute lung injury post COVID-19, and can promote lung repair mechanisms, that lead to a 25% improvement in lung oxygenation parameters. This hypothesis is based on experiments performed in mice showing that C5a blockade can prevent mortality and prevent ARDS in mice with post-viral acute lung injury. Eligible patients include patients with confirmed COVID-19 infection suffering from hypoxic respiratory failure defined as O2 saturation below 93% on minimal 2l/min O2 therapy and/or ratio PaO2/FiO2 below 350.
Detailed description
This investigator-initiated trial is a phase 2 academic, prospective, 2:1 randomized, open-label, multicenter interventional study designed to investigate the efficacy of subcutaneous Zilucoplan® in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure. The hypothesis of the proposed intervention is that Zilucoplan® has profound effects on inhibiting acute lung injury induced by COVID-19, and can promote lung repair mechanisms, that lead to a 25% improvement in lung oxygenation parameters. This hypothesis is based on experiments performed in mice showing that C5a blockade can prevent mortality and prevent ARDS in mice with post-viral acute lung injury. We will randomize patients with confirmed COVID19 with acute hypoxic respiratory failure (O2 saturation below 93% on minimal 2l/min O2 therapy; and/or PaO2/FiO2 below 350 mmHg) to receive up to 14 days of SC Zilucoplan® on top of standard of care (active group A), or to receive standard of care treatment (control group B). Randomization will be done at a 2:1 ratio active: control group. In the active group A, patients will additionally receive daily antibiotics (daily 3rd generation cephalosporin IV while in hospital, followed by oral ciprofloxacin while discharged) as primary prophylaxis against meningococcal disease until 14 days after the last dose of Zilucoplan®. Control group B will receive standard of care and prophylactic antibiotics (3rd generation cephalosporin IV) for only 1 week (or until hospital discharge whichever comes first), to control for the effects of antibiotics on the clinical course of COVID-19. In case of allergies to these antibiotics, or on clinical indication, these antibiotics may be switched to antibiotics that also cover Neisseria meningitidis. To measure the effectiveness of Zilucoplan® on restoring lung homeostasis, the primary endpoint of this intervention is measuring change in oxygenation parameters comparing baseline values (pretreatment) to values predose day 6 and to values at day 15 (or discharge whichever comes first) post-randomizationin group A and group B and the differences in these values between group A and group B.
Interventions
DRUGZilucoplan®
14 days of SC Zilucoplan® on top of standard of care + prophylactic antibiotics until 14 days after last Zilucoplan®
DRUGPlacebo
standard of care treatment + 1 week of prophylactic antibiotics (or until hospital discharge, whichever comes first)
Sponsors
UCB Pharma
University Hospital, Ghent
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Recent (≥6 days and ≤16 days of flu-like symptoms or malaise prior to randomization) infection with COVID-19. * COVID-19 diagnosis confirmed by antigen detection test and/or PCR and/or positive serology, or any emerging and validated diagnostic laboratory test for COVID-19 within this period. For patients with a negative SARS-CoV-2 PCR and either a positive SARS-CoV-2 antigen or antibody test, the presence of suggestive lesions for COVID-19 on chest-CT scan is mandatory. * In some patients, it may be impossible to get a confident laboratory confirmation of COVID-19 diagnosis after 24h of hospital admission because viral load is low and/or problems with diagnostic sensitivity. In those cases, in absence of an alternative diagnosis, and with highly suspect bilateral ground glass opacities on recent (\<24h) chest-CT scan (confirmed by a radiologist and pulmonary physician as probable COVID-19), and a typical clinical and chemical diagnosis with signs of cytokine release syndrome, a patient can be enrolled as probable SARS-CoV-2-infected. In all cases, this needs confirmation by later seroconversion. * Presence of hypoxia defined as : * O2 saturation below 93% on minimal 2l/min O2 therapy; and/or * PaO2/FiO2 below 350 mmHg (Strongly recommended: patient in upright position, after minimal 3 minutes without supplemental oxygen; In ventilated patients or ECMO patients PaO2 can be taken from invasive arterial line and FiO2 taken directly from mechanical ventilation settings). * Signs of acute lung injury and/or cytokine release syndrome defined as ANY of the following * serum ferritin concentration \>1000 mcg/L and rising since last 24h * single ferritin above 2000 mcg/L in patients requiring immediate high flow oxygen device (Optiflow) or non-invasive or invasive mechanical ventilation * lymphopenia defined as \<800 lymphocytes/microliter and two of the following extra criteria * Ferritin \> 700 mcg/L and rising since last 24h * Increased LDH (above 300 IU/L) and rising since last 24h * D-Dimers \> 1000 ng/mL and rising since last 24h * CRP above 70 mg/L and rising since last 24h and absence of bacterial infection * if three of the above are present at admission, no need to document 24h rise * Low dose Chest CT or HRCT or Angio Chest CT scan showing bilateral infiltrates within last 2 days prior to randomisation * Admitted to specialized COVID-19 ward or an ICU ward taking care of COVID-19 patients * Age ≥ 18 years * Women of childbearing potential must have a negative serum pregnancy test pre-dose on day 1. Women of childbearing potential must consistently and correctly use (during the entire treatment period and 4weeks after last Zilucoplan® administration ) at least 1 highly effective method for contraception. * Willing and able to provide informed consent or legal representative willing to provide informed consent
Exclusion criteria
* Patients with known history of serious allergic reactions, including anaphylaxis, to Zilucoplan® or inability to receive antibiotic prophylaxis due to allergy to ALL of the antibiotics that can be given for prophylaxis of meningococcal disease * History of active or past meningococcal disease * Invasive mechanical ventilation \> 24 h at randomization * Patient on ECMO at screening * Clinical frailty scale above 3 before onset of the COVID-19 episode * Weight below 54 kg as measured max 1 week prior to inclusion * Weight above 150 kg as measured max 1 week prior to inclusion * Active bacterial or fungal infection * Unlikely to survive beyond 48h * Neutrophil count below 1500 cells/microliter * Platelets below 50.000/microliter * Patients enrolled in another investigational drug study * Patients on high dose systemic steroids (\> 8 mg methylprednisolone or equivalent for more than 1 month) or other moderately immunosuppressive drugs (in the opinion of the investigator) for COVID19 unrelated disorder * Patients on current complement inhibiting drugs * Serum transaminase levels \>5 times upper limit of normal, unless there are clear signs of cytokine release syndrome defined by LDH \>300 IU/L and ferritin \>700 ng/ml * Pregnant or breastfeeding females (all female subjects deemed of childbearing potential by the investigator must have negative pregnancy test at screening)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Oxygenation | at predose, day 6 and day 15 (or at discharge, whichever comes first) | defined by Pa02/FiO2 ratio while breathing room air, P(Aa)O2 gradient and a/A pO2 ratio |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With SUSAR's (Suspected Unexpected Serious Adverse Reaction) | during hospital admission (up to 28 days) | A serious adverse reaction, the nature and severity of which is not consistent with the information about the medicinal product in question set out: * in the case of a product with a marketing authorisation, in the summary of product characteristics (SmPC) for that product * in the case of any other investigational medicinal product, in the investigator's brochure (IB) relating to the study in question |
| Result of 6 Minute Walk Test | at 12-22 weeks follow-up | Distance in 6 minute walk test. The 6 Minute Walk Test is a sub-maximal exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. Total distance in meters. A higher score has a better outcome |
| All-cause Mortality Rate (Excluding Group That Entered During Ventilation) | at day 28 | — |
| All-cause Mortality Rate (Including Group That Entered During Ventilation) | at day 28 | — |
| All Cause Mortality for the Entire Study Population | at follow up 12-22 weeks | — |
| Mean Change in 6-point Ordinal Scale Change for Clinical Improvement | between day 1 and respectively day 6, day 15 (or discharge, whichever comes first) and day 28 (by phone call). | 6-point ordinal scale defined as 1. Death 2. Hospitalized, on invasive mechanical ventilation or ECMO; 3. Hospitalized, on non-invasive ventilation 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, not requiring supplemental oxygen 6. Not hospitalized |
| Number of Days With Hypoxia | during hospital admission (up to 28 days) | defined as SpO2 \< 93% breathing room air or the dependence on supplemental oxygen |
| Number of Days of Supplemental Oxygen Use | during hospital admission (up to 28 days) | — |
| Time to Absence of Fever (Defined as 37.1°C or More) for More Than 48h Without Antipyretic | during hospital admission (up to 28 days) | — |
| Number of Days With Fever | during hospital admission (up to 28 days) | defined as 37.1°C or more |
| Mean Change in CRP Levels Between Day 1 and Day 6 | day 1, day 6 | — |
| Mean Change in CRP Levels Between Day 1 and Day 15 (or Discharge Whichever Comes First) | day 1, day 15 | — |
| Mean Change in Ferritin Levels Between Day 1 and Day 6 | day 1, day 6 | — |
| Mean Change in Ferritin Levels Between Day 1 and Day 15 (or Discharge, Whichever Comes First) | day 1, day 15 | — |
| Number of Participants With Adverse Events | during hospital admission (up to 28 days) | Any untoward medical occurrence in a subject to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. |
| Number of Participants With Serious Adverse Events | at 10-20 weeks follow-up | A serious adverse event is any untoward medical occurrence that: * results in death * is life-threatening * requires inpatient hospitalisation or prolongation of existing hospitalisation * results in persistent or significant disability/incapacity * consists of a congenital anomaly or birth defect Other 'important medical events' may also be considered serious if they jeopardise the subject or require an intervention to prevent one of the above consequences. NOTE: The term life-threatening in the definition of serious refers to an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. |
| Number of Participants With SAR's (Serious Adverse Reaction) | during hospital admission (up to 28 days) | An adverse event that is both serious and, in the opinion of the reporting Investigator, believed with reasonable probability to be due to one of the study treatments, based on the information provided. |
| Duration of Hospital Stay | at 12-22 weeks follow-up | — |
| Duration of Hospital Stay in Survivors | at 12-22 weeks follow-up | — |
| Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 6 (or on Discharge, Whichever is First) | day 1, day 6 or on discharge, whichever is first | The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems (respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems). Score ranges from 0 (best) to 24 (worst) points. |
| Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 15 (or on Discharge, Whichever is First) | day 1, day 15 or on discharge, whichever is first | The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems (respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems). Score ranges from 0 (best) to 24 (worst) points. |
| Number of Participants With Nosocomial Bacterial or Invasive Fungal Infection for 28 Days (Phone Call) After Enrollment in Trial | day 28 | — |
| Median Time to at Least a 2-point Improvement on the 6-point Ordinal Scale or Discharge During the 28-day Assessment Period (Range) - Days | Day 28 | The 6-point ordinal scale for clinical improvement is defined as 1 = Death; 2 = Hospitalized, on invasive mechanical ventilation or ECMO; 3 = Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4 = Hospitalized, requiring supplemental oxygen; 5 = Hospitalized, not requiring supplemental oxygen; 6 = Not hospitalized. A higher score represent a better outcome |
| Number of Participants in Each Category of the 6- Point Ordinal Scale for Clinical Improvement | at 12-22 weeks follow-up | The 6-point ordinal scale for clinical improvement is defined as 1 = Death; 2 = Hospitalized, on invasive mechanical ventilation or ECMO; 3 = Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4 = Hospitalized, requiring supplemental oxygen; 5 = Hospitalized, not requiring supplemental oxygen; 6 = Not hospitalized. A higher score represent a better outcome |
| Number of Participants in Each Category of the WHO Performance Scale | during hospital admission (up to 28 days) | The WHO performance status classification categorises patients as: 0: able to carry out all normal activity without restriction 1. restricted in strenuous activity but ambulatory and able to carry out light work 2. ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours 3. symptomatic and in a chair or in bed for greater than 50% of the day but not bedridden 4. completely disabled; cannot carry out any self-care; totally confined to bed or chair. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Time Since Randomization to Progression to ARDS (Acute Respiratory Distress Syndrome) | during hospital admission (up to 28 days) | criteria-defined ARDS criteria-defined ARDS according to the adapted Berlin criteria as follow: * within 1 week of a known Clinical insult or new or worsening respiratory symptoms * bilateral infiltrates not supposed to be of cardiac origin or fluid overload * PaO2/FiO2 \< 300 mmHg |
| Number of Participants With Lung Fibrosis on Chest CT Scan at Follow up | at 12-22 weeks follow-up | — |
| Number of Ventilator-free Days | day 1, day 28 or discharge whichever comes first | — |
| Time Since Randomization Until Improvement in Oxygenation | during hospital admission (up to 28 days) | defined as independence from supplemental oxygen |
Countries
Belgium
Participant flow
Pre-assignment details
81 patients were randomized at the 9 participating centers.
Participants by arm
| Arm | Count |
|---|---|
| Group A (Active) Standard of Care (SoC) + subcutaneous Zilucoplan® + prophylactic antibiotics until 14 days after last Zilucoplan®
Zilucoplan®: 14 days of SC Zilucoplan® on top of standard of care + prophylactic antibiotics until 14 days after last Zilucoplan® | 54 |
| Group B (Control) Standard of Care (SoC) + 1 week of prophylactic antibiotics (or until hospital discharge, whichever comes first)
Placebo: standard of care treatment + 1 week of prophylactic antibiotics + 1 week of prophylactic antibiotics (or until hospital discharge, whichever comes first) | 24 |
| Total | 78 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | did not meet inclusion criteria but was randomized without receiving the allocated intervention | 0 | 1 |
| Overall Study | did not receive allocated intervention due to clinical error | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Group A (Active) | Group B (Control) | Total |
|---|---|---|---|
| A-a gradient at baseline | 271.8 mmHg STANDARD_DEVIATION 211.1 | 237.2 mmHg STANDARD_DEVIATION 207.8 | 260.6 mmHg STANDARD_DEVIATION 209.2 |
| Admitted to ICU at randomisation | 30 Participants | 12 Participants | 42 Participants |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 25 Participants | 12 Participants | 37 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants | 12 Participants | 41 Participants |
| Age, Continuous | 62 years | 64.8 years | 63 years |
| Antibiotics at randomisation no | 38 Participants | 22 Participants | 60 Participants |
| Antibiotics at randomisation yes | 16 Participants | 2 Participants | 18 Participants |
| Anticoagulants at randomisation no | 5 Participants | 3 Participants | 8 Participants |
| Anticoagulants at randomisation yes | 49 Participants | 21 Participants | 70 Participants |
| Arterial hypertension no | 28 Participants | 14 Participants | 42 Participants |
| Arterial hypertension yes | 26 Participants | 10 Participants | 36 Participants |
| Cardiovascular disease no | 45 Participants | 14 Participants | 59 Participants |
| Cardiovascular disease yes | 9 Participants | 10 Participants | 19 Participants |
| Chronic kidney disease no | 50 Participants | 24 Participants | 74 Participants |
| Chronic kidney disease yes | 4 Participants | 0 Participants | 4 Participants |
| Days of hospitalization at randomisation | 3 days | 2 days | 2 days |
| Days of symptoms at randomisation | 10 days | 10 days | 10 days |
| Diabetes mellitus no | 28 Participants | 14 Participants | 42 Participants |
| Diabetes mellitus yes | 26 Participants | 10 Participants | 36 Participants |
| Ethnicity African | 4 Participants | 0 Participants | 4 Participants |
| Ethnicity Arabian | 3 Participants | 1 Participants | 4 Participants |
| Ethnicity Asian | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity Caucasian | 46 Participants | 22 Participants | 68 Participants |
| Ethnicity Other | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 54 Participants | 23 Participants | 77 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Glucocorticoids at randomisation no | 5 Participants | 6 Participants | 11 Participants |
| Glucocorticoids at randomisation yes | 49 Participants | 18 Participants | 67 Participants |
| glucocorticoid use during first 28 days no | 2 Participants | 3 Participants | 5 Participants |
| glucocorticoid use during first 28 days yes | 52 Participants | 21 Participants | 73 Participants |
| Ordinal scale for clinical improvement 2. on invasive mechanical ventilation of ECMO | 8 Participants | 2 Participants | 10 Participants |
| Ordinal scale for clinical improvement 3. on non-invasive ventilation of high flow oxygen devices | 19 Participants | 8 Participants | 27 Participants |
| Ordinal scale for clinical improvement 4. hospitalized, requiring supplemental oxygen | 26 Participants | 14 Participants | 40 Participants |
| Ordinal scale for clinical improvement 5. hospitalized, not requiring supplemental oxygen | 1 Participants | 0 Participants | 1 Participants |
| PaO2/FiO2 ratio at baseline | 169.2 mmHG STANDARD_DEVIATION 93.8 | 175.1 mmHG STANDARD_DEVIATION 92.5 | 171.1 mmHG STANDARD_DEVIATION 92.8 |
| Remdesivir at randomisation no | 47 Participants | 22 Participants | 69 Participants |
| Remdesivir at randomisation yes | 7 Participants | 2 Participants | 9 Participants |
| Sequential Organ Failure Assessment (SOFA score) score 1-2 | 29 Participants | 14 Participants | 43 Participants |
| Sequential Organ Failure Assessment (SOFA score) score 3-4 | 14 Participants | 7 Participants | 21 Participants |
| Sequential Organ Failure Assessment (SOFA score) score 5-6 | 1 Participants | 2 Participants | 3 Participants |
| Sequential Organ Failure Assessment (SOFA score) score 7-8 | 7 Participants | 0 Participants | 7 Participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 49 Participants | 19 Participants | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 7 / 54 | 5 / 24 |
| other Total, other adverse events | 39 / 54 | 17 / 24 |
| serious Total, serious adverse events | 10 / 54 | 5 / 24 |
Outcome results
Primary
Change in Oxygenation
defined by Pa02/FiO2 ratio while breathing room air, P(Aa)O2 gradient and a/A pO2 ratio
Time frame: at predose, day 6 and day 15 (or at discharge, whichever comes first)
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Group A (Active) | Change in Oxygenation | change from baseline in PaO2/FiO2 day 6 | 56.4 mmHg |
| Group A (Active) | Change in Oxygenation | change from baseline in PaO2/FiO2 day 15 | 123.5 mmHg |
| Group A (Active) | Change in Oxygenation | change from baseline in a/A PO2 day 6 | 0.10 mmHg |
| Group A (Active) | Change in Oxygenation | change from baseline in a/A PO2 day 15 | 0.25 mmHg |
| Group B (Control) | Change in Oxygenation | change from baseline in a/A PO2 day 15 | 0.17 mmHg |
| Group B (Control) | Change in Oxygenation | change from baseline in PaO2/FiO2 day 6 | 20.6 mmHg |
| Group B (Control) | Change in Oxygenation | change from baseline in a/A PO2 day 6 | 0.04 mmHg |
| Group B (Control) | Change in Oxygenation | change from baseline in PaO2/FiO2 day 15 | 83.7 mmHg |
Primary
Change in Oxygenation
defined by Pa02/FiO2 ratio while breathing room air, P(Aa)O2 gradient and a/A pO2 ratio
Time frame: at predose, day 6 and day 15 (or at discharge, whichever comes first)
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Group A (Active) | Change in Oxygenation | (A-a) gradient day 6 | 114.6 mmHg |
| Group A (Active) | Change in Oxygenation | (A-a) gradient day 15 | 58.6 mmHg |
| Group B (Control) | Change in Oxygenation | (A-a) gradient day 6 | 146.7 mmHg |
| Group B (Control) | Change in Oxygenation | (A-a) gradient day 15 | 86.9 mmHg |
Secondary
All Cause Mortality for the Entire Study Population
Time frame: at follow up 12-22 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A (Active) | All Cause Mortality for the Entire Study Population | 7 Participants |
| Group B (Control) | All Cause Mortality for the Entire Study Population | 5 Participants |
Secondary
All-cause Mortality Rate (Excluding Group That Entered During Ventilation)
Time frame: at day 28
Population: Population excluding patients that required invasive mechanical ventilation or ECMO within 24 hours prior to or after randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A (Active) | All-cause Mortality Rate (Excluding Group That Entered During Ventilation) | 3 Participants |
| Group B (Control) | All-cause Mortality Rate (Excluding Group That Entered During Ventilation) | 5 Participants |
Secondary
All-cause Mortality Rate (Including Group That Entered During Ventilation)
Time frame: at day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A (Active) | All-cause Mortality Rate (Including Group That Entered During Ventilation) | 5 Participants |
| Group B (Control) | All-cause Mortality Rate (Including Group That Entered During Ventilation) | 5 Participants |
Secondary
Duration of Hospital Stay
Time frame: at 12-22 weeks follow-up
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Active) | Duration of Hospital Stay | 15 days |
| Group B (Control) | Duration of Hospital Stay | 13 days |
Secondary
Duration of Hospital Stay in Survivors
Time frame: at 12-22 weeks follow-up
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Active) | Duration of Hospital Stay in Survivors | 15 days |
| Group B (Control) | Duration of Hospital Stay in Survivors | 12 days |
Secondary
Mean Change in 6-point Ordinal Scale Change for Clinical Improvement
6-point ordinal scale defined as 1. Death 2. Hospitalized, on invasive mechanical ventilation or ECMO; 3. Hospitalized, on non-invasive ventilation 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, not requiring supplemental oxygen 6. Not hospitalized
Time frame: between day 1 and respectively day 6, day 15 (or discharge, whichever comes first) and day 28 (by phone call).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A (Active) | Mean Change in 6-point Ordinal Scale Change for Clinical Improvement | mean change in 6-point ordinal scale change day 6 | 0.1 score on a scale | Standard Deviation 1 |
| Group A (Active) | Mean Change in 6-point Ordinal Scale Change for Clinical Improvement | mean change in 6-point ordinal scale change day 15 | 1.2 score on a scale | Standard Deviation 1.4 |
| Group A (Active) | Mean Change in 6-point Ordinal Scale Change for Clinical Improvement | mean change in 6-point ordinal scale change day 28 | 1.7 score on a scale | Standard Deviation 1.5 |
| Group B (Control) | Mean Change in 6-point Ordinal Scale Change for Clinical Improvement | mean change in 6-point ordinal scale change day 6 | 0.1 score on a scale | Standard Deviation 0.9 |
| Group B (Control) | Mean Change in 6-point Ordinal Scale Change for Clinical Improvement | mean change in 6-point ordinal scale change day 15 | 1 score on a scale | Standard Deviation 1.5 |
| Group B (Control) | Mean Change in 6-point Ordinal Scale Change for Clinical Improvement | mean change in 6-point ordinal scale change day 28 | 1.3 score on a scale | Standard Deviation 1.8 |
Secondary
Mean Change in CRP Levels Between Day 1 and Day 15 (or Discharge Whichever Comes First)
Time frame: day 1, day 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A (Active) | Mean Change in CRP Levels Between Day 1 and Day 15 (or Discharge Whichever Comes First) | -91.0 mg/mL | Standard Deviation 106.3 |
| Group B (Control) | Mean Change in CRP Levels Between Day 1 and Day 15 (or Discharge Whichever Comes First) | -96.2 mg/mL | Standard Deviation 98.4 |
Secondary
Mean Change in CRP Levels Between Day 1 and Day 6
Time frame: day 1, day 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A (Active) | Mean Change in CRP Levels Between Day 1 and Day 6 | -89.6 mg/mL | Standard Deviation 91.5 |
| Group B (Control) | Mean Change in CRP Levels Between Day 1 and Day 6 | -100 mg/mL | Standard Deviation 61.9 |
Secondary
Mean Change in Ferritin Levels Between Day 1 and Day 15 (or Discharge, Whichever Comes First)
Time frame: day 1, day 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A (Active) | Mean Change in Ferritin Levels Between Day 1 and Day 15 (or Discharge, Whichever Comes First) | -201.0 µg/L | Standard Deviation 6204.5 |
| Group B (Control) | Mean Change in Ferritin Levels Between Day 1 and Day 15 (or Discharge, Whichever Comes First) | -303.9 µg/L | Standard Deviation 948.4 |
Secondary
Mean Change in Ferritin Levels Between Day 1 and Day 6
Time frame: day 1, day 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A (Active) | Mean Change in Ferritin Levels Between Day 1 and Day 6 | -544.4 µg/L | Standard Deviation 1489.9 |
| Group B (Control) | Mean Change in Ferritin Levels Between Day 1 and Day 6 | -282.3 µg/L | Standard Deviation 517 |
Secondary
Median Time to at Least a 2-point Improvement on the 6-point Ordinal Scale or Discharge During the 28-day Assessment Period (Range) - Days
The 6-point ordinal scale for clinical improvement is defined as 1 = Death; 2 = Hospitalized, on invasive mechanical ventilation or ECMO; 3 = Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4 = Hospitalized, requiring supplemental oxygen; 5 = Hospitalized, not requiring supplemental oxygen; 6 = Not hospitalized. A higher score represent a better outcome
Time frame: Day 28
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Active) | Median Time to at Least a 2-point Improvement on the 6-point Ordinal Scale or Discharge During the 28-day Assessment Period (Range) - Days | 15 days |
| Group B (Control) | Median Time to at Least a 2-point Improvement on the 6-point Ordinal Scale or Discharge During the 28-day Assessment Period (Range) - Days | 12 days |
Secondary
Number of Days of Supplemental Oxygen Use
Time frame: during hospital admission (up to 28 days)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Active) | Number of Days of Supplemental Oxygen Use | 13 days |
| Group B (Control) | Number of Days of Supplemental Oxygen Use | 10 days |
Secondary
Number of Days With Fever
defined as 37.1°C or more
Time frame: during hospital admission (up to 28 days)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Active) | Number of Days With Fever | 7 days |
| Group B (Control) | Number of Days With Fever | 4 days |
Secondary
Number of Days With Hypoxia
defined as SpO2 \< 93% breathing room air or the dependence on supplemental oxygen
Time frame: during hospital admission (up to 28 days)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Active) | Number of Days With Hypoxia | 13 days |
| Group B (Control) | Number of Days With Hypoxia | 10 days |
Secondary
Number of Participants in Each Category of the 6- Point Ordinal Scale for Clinical Improvement
The 6-point ordinal scale for clinical improvement is defined as 1 = Death; 2 = Hospitalized, on invasive mechanical ventilation or ECMO; 3 = Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4 = Hospitalized, requiring supplemental oxygen; 5 = Hospitalized, not requiring supplemental oxygen; 6 = Not hospitalized. A higher score represent a better outcome
Time frame: at 12-22 weeks follow-up
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Active) | Number of Participants in Each Category of the 6- Point Ordinal Scale for Clinical Improvement | category 3 | 0 Participants |
| Group A (Active) | Number of Participants in Each Category of the 6- Point Ordinal Scale for Clinical Improvement | category 5 | 0 Participants |
| Group A (Active) | Number of Participants in Each Category of the 6- Point Ordinal Scale for Clinical Improvement | category 4 | 1 Participants |
| Group A (Active) | Number of Participants in Each Category of the 6- Point Ordinal Scale for Clinical Improvement | category 6 | 43 Participants |
| Group A (Active) | Number of Participants in Each Category of the 6- Point Ordinal Scale for Clinical Improvement | category 2 | 0 Participants |
| Group B (Control) | Number of Participants in Each Category of the 6- Point Ordinal Scale for Clinical Improvement | category 6 | 19 Participants |
| Group B (Control) | Number of Participants in Each Category of the 6- Point Ordinal Scale for Clinical Improvement | category 2 | 0 Participants |
| Group B (Control) | Number of Participants in Each Category of the 6- Point Ordinal Scale for Clinical Improvement | category 3 | 0 Participants |
| Group B (Control) | Number of Participants in Each Category of the 6- Point Ordinal Scale for Clinical Improvement | category 4 | 0 Participants |
| Group B (Control) | Number of Participants in Each Category of the 6- Point Ordinal Scale for Clinical Improvement | category 5 | 0 Participants |
Secondary
Number of Participants in Each Category of the WHO Performance Scale
The WHO performance status classification categorises patients as: 0: able to carry out all normal activity without restriction 1. restricted in strenuous activity but ambulatory and able to carry out light work 2. ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours 3. symptomatic and in a chair or in bed for greater than 50% of the day but not bedridden 4. completely disabled; cannot carry out any self-care; totally confined to bed or chair.
Time frame: during hospital admission (up to 28 days)
Population: For 1 participant of group A and 1 participant of group B, the WHO performance scale was not recorded.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Active) | Number of Participants in Each Category of the WHO Performance Scale | category 0 | 23 Participants |
| Group A (Active) | Number of Participants in Each Category of the WHO Performance Scale | category 1 | 18 Participants |
| Group A (Active) | Number of Participants in Each Category of the WHO Performance Scale | category >=2 | 2 Participants |
| Group B (Control) | Number of Participants in Each Category of the WHO Performance Scale | category 0 | 10 Participants |
| Group B (Control) | Number of Participants in Each Category of the WHO Performance Scale | category 1 | 7 Participants |
| Group B (Control) | Number of Participants in Each Category of the WHO Performance Scale | category >=2 | 1 Participants |
Secondary
Number of Participants With Adverse Events
Any untoward medical occurrence in a subject to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Time frame: during hospital admission (up to 28 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A (Active) | Number of Participants With Adverse Events | 39 Participants |
| Group B (Control) | Number of Participants With Adverse Events | 17 Participants |
Secondary
Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 15 (or on Discharge, Whichever is First)
The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems (respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems). Score ranges from 0 (best) to 24 (worst) points.
Time frame: day 1, day 15 or on discharge, whichever is first
Population: Change of SOFA score between day 1 and day 15
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Active) | Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 15 (or on Discharge, Whichever is First) | improvement or discharge | 33 Participants |
| Group A (Active) | Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 15 (or on Discharge, Whichever is First) | no change | 5 Participants |
| Group A (Active) | Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 15 (or on Discharge, Whichever is First) | death or deterioration | 5 Participants |
| Group B (Control) | Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 15 (or on Discharge, Whichever is First) | improvement or discharge | 12 Participants |
| Group B (Control) | Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 15 (or on Discharge, Whichever is First) | no change | 1 Participants |
| Group B (Control) | Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 15 (or on Discharge, Whichever is First) | death or deterioration | 4 Participants |
Secondary
Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 6 (or on Discharge, Whichever is First)
The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems (respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems). Score ranges from 0 (best) to 24 (worst) points.
Time frame: day 1, day 6 or on discharge, whichever is first
Population: Change of SOFA score between day 1 and day 6
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Active) | Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 6 (or on Discharge, Whichever is First) | improvement or discharge | 21 Participants |
| Group A (Active) | Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 6 (or on Discharge, Whichever is First) | no change | 11 Participants |
| Group A (Active) | Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 6 (or on Discharge, Whichever is First) | death or deterioration | 11 Participants |
| Group B (Control) | Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 6 (or on Discharge, Whichever is First) | improvement or discharge | 10 Participants |
| Group B (Control) | Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 6 (or on Discharge, Whichever is First) | no change | 6 Participants |
| Group B (Control) | Number of Participants With Improvement, No Change, Death or Deterioration in SOFA Score Between Day 1 and Day 6 (or on Discharge, Whichever is First) | death or deterioration | 5 Participants |
Secondary
Number of Participants With Nosocomial Bacterial or Invasive Fungal Infection for 28 Days (Phone Call) After Enrollment in Trial
Time frame: day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A (Active) | Number of Participants With Nosocomial Bacterial or Invasive Fungal Infection for 28 Days (Phone Call) After Enrollment in Trial | 12 Participants |
| Group B (Control) | Number of Participants With Nosocomial Bacterial or Invasive Fungal Infection for 28 Days (Phone Call) After Enrollment in Trial | 4 Participants |
Secondary
Number of Participants With SAR's (Serious Adverse Reaction)
An adverse event that is both serious and, in the opinion of the reporting Investigator, believed with reasonable probability to be due to one of the study treatments, based on the information provided.
Time frame: during hospital admission (up to 28 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A (Active) | Number of Participants With SAR's (Serious Adverse Reaction) | 0 Participants |
| Group B (Control) | Number of Participants With SAR's (Serious Adverse Reaction) | 0 Participants |
Secondary
Number of Participants With Serious Adverse Events
A serious adverse event is any untoward medical occurrence that: * results in death * is life-threatening * requires inpatient hospitalisation or prolongation of existing hospitalisation * results in persistent or significant disability/incapacity * consists of a congenital anomaly or birth defect Other 'important medical events' may also be considered serious if they jeopardise the subject or require an intervention to prevent one of the above consequences. NOTE: The term life-threatening in the definition of serious refers to an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.
Time frame: at 10-20 weeks follow-up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A (Active) | Number of Participants With Serious Adverse Events | 10 Participants |
| Group B (Control) | Number of Participants With Serious Adverse Events | 5 Participants |
Secondary
Number of Participants With SUSAR's (Suspected Unexpected Serious Adverse Reaction)
A serious adverse reaction, the nature and severity of which is not consistent with the information about the medicinal product in question set out: * in the case of a product with a marketing authorisation, in the summary of product characteristics (SmPC) for that product * in the case of any other investigational medicinal product, in the investigator's brochure (IB) relating to the study in question
Time frame: during hospital admission (up to 28 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A (Active) | Number of Participants With SUSAR's (Suspected Unexpected Serious Adverse Reaction) | 0 Participants |
| Group B (Control) | Number of Participants With SUSAR's (Suspected Unexpected Serious Adverse Reaction) | 0 Participants |
Secondary
Result of 6 Minute Walk Test
Distance in 6 minute walk test. The 6 Minute Walk Test is a sub-maximal exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. Total distance in meters. A higher score has a better outcome
Time frame: at 12-22 weeks follow-up
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A (Active) | Result of 6 Minute Walk Test | 539.7 meters | Standard Deviation 107.7 |
| Group B (Control) | Result of 6 Minute Walk Test | 490.6 meters | Standard Deviation 0.18 |
Secondary
Time to Absence of Fever (Defined as 37.1°C or More) for More Than 48h Without Antipyretic
Time frame: during hospital admission (up to 28 days)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Active) | Time to Absence of Fever (Defined as 37.1°C or More) for More Than 48h Without Antipyretic | 7 days |
| Group B (Control) | Time to Absence of Fever (Defined as 37.1°C or More) for More Than 48h Without Antipyretic | 3 days |
Other Pre-specified
Number of Participants With Lung Fibrosis on Chest CT Scan at Follow up
Time frame: at 12-22 weeks follow-up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A (Active) | Number of Participants With Lung Fibrosis on Chest CT Scan at Follow up | 0 Participants |
| Group B (Control) | Number of Participants With Lung Fibrosis on Chest CT Scan at Follow up | 0 Participants |
Other Pre-specified
Number of Ventilator-free Days
Time frame: day 1, day 28 or discharge whichever comes first
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Active) | Number of Ventilator-free Days | 7 days |
| Group B (Control) | Number of Ventilator-free Days | 9 days |
Other Pre-specified
Time Since Randomization to Progression to ARDS (Acute Respiratory Distress Syndrome)
criteria-defined ARDS criteria-defined ARDS according to the adapted Berlin criteria as follow: * within 1 week of a known Clinical insult or new or worsening respiratory symptoms * bilateral infiltrates not supposed to be of cardiac origin or fluid overload * PaO2/FiO2 \< 300 mmHg
Time frame: during hospital admission (up to 28 days)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Active) | Time Since Randomization to Progression to ARDS (Acute Respiratory Distress Syndrome) | 1 days |
| Group B (Control) | Time Since Randomization to Progression to ARDS (Acute Respiratory Distress Syndrome) | 3 days |
Other Pre-specified
Time Since Randomization Until Improvement in Oxygenation
defined as independence from supplemental oxygen
Time frame: during hospital admission (up to 28 days)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Active) | Time Since Randomization Until Improvement in Oxygenation | 13 days |
| Group B (Control) | Time Since Randomization Until Improvement in Oxygenation | 10 days |