Acute Respiratory Distress Syndrome
Conditions
Brief summary
This is a study in adults with severe breathing problems because of COVID-19. People who are in hospital on breathing support can participate in the study. The purpose of the study is to find out whether a medicine called alteplase helps people get better faster. The study has 2 parts. In the first part, participants are put into 3 groups by chance. Participants in 2 of the groups get 2 different doses of alteplase, in addition to standard treatment. Participants in the third group get standard treatment. In the second part of the study, participants are put into 2 groups by chance. One group gets alteplase and standard treatment. The other group gets only standard treatment. Alteplase is given as an infusion into a vein. In both study parts, treatments are given for 5 days. Doctors monitor patients and check whether their breathing problems improve. They compare results between the groups after 1 month. Participants are in the study for 3 months.
Interventions
PROCEDUREStandard of care
Standard of Care (SOC) includes any supportive measures applied in hospital, specifically on an intensive care unit (ICU), such as for example the use of non-invasive or invasive ventilation, oxygen masks, haemodynamic support, if needed, sedation, as well as medical therapies commonly used in patients suffering from acute respiratory distress syndrome (ARDS) or its complications. SOC should include best possible treatment regimen established locally and should be in line with current guidelines for ARDS treatment.
DRUGAlteplase low dose
0.3 milligram/kilogram (mg/kg) over 2 hours (Day 1) immediately followed by daily infusion of 0.02 mg/kg/hour over 12 hours (starting on Day 1 and up to Day 5). One optional additional infusion of 0.3 mg/kg over 2 hours could be given once on Days 2 to 5 in case of clinical worsening, per investigator judgement.
DRUGAlteplase high dose
0.6 milligram/kilogram (mg/kg) over 2 hours (Day 1) immediately followed by daily infusion of 0.04 mg/kg/hour over 12 hours (starting on Day 1 and up to Day 5). One optional additional infusion of 0.6 mg/kg over 2 hours could be given once on Days 2 to 5 in case of clinical worsening, per investigator judgement.
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The study comprises two parts: Part 1 (dose-finding, Phase IIb) and Part 2 (confirmatory, Phase III)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years (or above legal age, e.g. UK ≥16 years) * ARDS with PaO2\*/FiO2 ratio \>100 and ≤300, either on non-invasive ventilator support, OR on mechanical ventilation (\<48 hours since intubation), * with bilateral opacities in chest X-ray or CT scan (not fully explained by effusions, lobar/lung collapse, or nodules) * with respiratory failure (not fully explained by cardiac failure/fluid overload) (\*or estimation of PaO2/FiO2 from pulse oximetry (SpO2/FiO2)) * SARS-CoV-2 positive (laboratory-confirmed reverse transcription polymerase chain reaction (RT PCR) test) * Fibrinogen level ≥ lower limit of normal (according to local laboratory) * D-Dimer ≥ upper limit of normal (ULN) according to local laboratory * Signed and dated written informed consent in accordance with ICH Good Clinical Practice (GCP) and local legislation prior to admission to the Trial
Exclusion criteria
* Massive confirmed pulmonary embolism (PE) with haemodynamic instability at trial entry, or any (suspected or confirmed) PE that is expected to require therapeutic dosages of anticoagulants during the treatment period * Indication for therapeutic dosages of anticoagulants at trial entry * Patients on mechanical ventilation for longer than 48 hours * Chronic pulmonary disease i.e. with known forced expiratory volume in 1 second (FEV1) \<50%, requiring home oxygen, or oral steroid therapy or hospitalisation for exacerbation within 12 months, or significant chronic pulmonary disease in the Investigator's opinion, or primary pulmonary arterial hypertension * Has a Do-Not-Intubate (DNI) or Do-Not-Resuscitate (DNR) order * In the opinion of the investigator not expected to survive for \> 48 hours after admission * Planned interventions during the first 5 days after randomisation, such as surgery, insertion of central catheter or arterial line, drains, etc. * Patients with known hypersensitivity to the active substance alteplase, gentamicin (a trace residue from the manufacturing process) or to any of the excipients * Significant bleeding disorder at present or within the past 3 months, known haemorrhagic diathesis * Patients receiving effective oral anticoagulant treatment, e.g. vitamin K antagonists with International normalised ratio (INR) \>1.3, or any direct oral anticoagulant within the past 48 hours Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Clinical Improvement or Hospital Discharge up to Day 28 | Up to 28 days. | From randomisation to either an improvement of 2 points on the 11-point World Health Organization (WHO) Clinical Progression Scale (from 0 to 10, a low score indicates a better outcome) or discharge from the hospital, whichever comes first. Full scale: 0=Uninfected; no viral RNA detected 1. Asymptomatic; viral RNA detected 2. Symptomatic; independent 3. Symptomatic; assistance needed 4. Hospitalised; no oxygen therapy 5. Hospitalised; oxygen by mask or nasal prongs 6. Hospitalised; oxygen by NIV or high flow 7. Intubation and mechanical ventilation, PaO2/FiO2=150 or SpO2/FiO2=200 8. Mechanical ventilation PaO2/FiO2\<150 (SpO2/FiO2\<200) or vasopressors 9. Mechanical ventilation PaO2/FiO2\<150 and vasopressors, dialysis, or ECMO 10. Dead Patients that have not met the endpoint were censored at Day 28 if they died prior to Day 28. Patients receiving bail out therapy without having first met the endpoint, were censored on the day of bail-out (hypothetical estimand). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All Cause Mortality at Day 28 | Up to 28 days. | All cause mortality at Day 28. If it is unknown whether the patient was dead at end of Day 28, then it will be assumed that the patient did not die up to Day 28, regardless of the reason. This unfavorable endpoint is met if: * the last known status of the patient is 10 on the WHO clinical progression scale by the end of Day 28, or * vital status is dead within 28 days |
| Number of Subjects With Treatment Failure at Day 28 | Up to 28 days. | Treatment failure defined as all cause mortality or mechanical ventilation at Day 28. |
| Number of Ventilator-free Days at Day 28 | Up to 28 days. | Number of ventilator-free days (VFDs) from start of treatment to Day 28. 'Ventilator' is defined as 'assisted breathing' but it refers to mechanical invasive ventilation. The number of VFDs starts from when the patient has a 'lasting' value on the WHO clinical progression scale of ≤ 6, and ends on Day 28. A lasting value of ≤ 6 means that the value cannot exceed 6 at a later timepoint. If the patient is liberated from the ventilator on Day x, then the number of VFDs is 28-x. If a patient has withdrawn consent prior to day 28 then he will have a missing value for VFD. In any case, if the status of the patient at Day 28 is death, as determined from the vital status page then the VFD=0. |
| Number of Subjects With Improvement of Sequential (Sepsis-related) Organ Failure Assessment (SOFA) Score by ≥2 Points at Day 6 | Baseline (Day 0) and Day 6 of treatment | Number of subjects with improvement of Sequential (sepsis-related) Organ Failure Assessment (SOFA) score by ≥2 points from baseline to end of Day 6. The Sequential Organ Failure Assessment (SOFA) scores six variables: respiratory, coagulation, liver, Cardiovascular, central nervous system and renal. Each variable is score from 0 (best outcome) to 4 (worst outcome) with a total score calculated as the sum of all six variables ranging from 0 (best outcome) to 24 (worst outcome). |
| Number of Subjects With Major Bleeding Events (MBE) at Day 6 | From start of treatment (Alteplase) or randomisation (SOC) (day 1) till Day 6, up to 6 days. | Number of subjects with major bleeding events (MBE). Major bleeding events (MBE) according to International Society on Thrombosis and Haemostasis \[ISTH\] definition until Day 6. Definition of a major bleed: •Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or •Bleeding associated with a reduction in hemoglobin of at least 2 gram/deciliter (1.24 millimole/Liter), or leading to transfusion of two or more units of blood or packed cells and/or •Fatal bleed |
| Number of Oxygen-free Days up to Day 28 | Up to 28 days. | Number of oxygen-free days (OFD) up to Day 28. Oxygen-free is defined as free from assistance from oxygen support. The number of oxygen-free days starts from when the patient has a 'lasting' value on the WHO clinical progression scale of ≤ 4 and ends on Day 28. A lasting value of ≤ 4 means that the value cannot exceed 4 at a later timepoint. If the patient is liberated from oxygen on Day x, then the number of OFDs is 28-x. If a patient has withdrawn consent prior to day 28 then he will have a missing value for OFD. In any case, if the status of the patient at Day 28 is death, as determined from the vital status page then the OFD=0. |
| Length of Hospital Stay up to Day 28 | Up to 28 days. | Length of hospital stay up to day 28 was determined based upon the first hospital discharge date, or discharge to another care facility. If the patient died within the first 28 day period, then length of hospital stay was 28. |
| Worst PaO2/FiO2 Ratio Change From Baseline to Day 6 | Up to 7 days. | Worst PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change from baseline to day 6. This assessment was planned to be measured on each of days 0 to 6. but only whilst the patients was still in hospital. The worst (lowest) daily measurement will be used and the higher the value the better the health status of the patient. * If the patient was still in hospital during day 6 then the day 6 value was used * If the patient was discharged from hospital prior to day 6 then the value at the time of hospital discharge was used * If the patient died prior to day 6 then the last value prior to death was used * If day 6 value was missing but Day 5 value available, the day 5 value was used * If day 6 value was missing, no Day 5 value available, but day 7 available, then day 7 value was used * Otherwise value was set to missing for that patient. Based upon this, the change from baseline for each patient was calculated and used for the analysis. |
| Daily Average PaO2/FiO2 Ratio Change From Baseline to Day 6 | Up to 6 days. | Daily average PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change from baseline to Day 6. This assessment was measured approximately 3-times daily. All available values on each of these days, regardless of the position of the patient when being measured, were averaged in order to determine the daily average PaO2/FiO2 ratio for that patient. The higher the value the better the health status of the patient. If the patient was still in hospital during day 6 then the day 6 daily average value was used, if available. If the patient was discharged from hospital prior to day 6 then the daily average at the time of hospital discharge was used as a surrogate for day 6, if available. If the patient died prior to day 6 then there was no imputation but the death handled as failure in the determination of the difference in medians and 95% CI. Based upon this, the change from baseline for each patient was calculated. |
Countries
Austria, Belgium, Brazil, France, Germany, India, Italy, Malaysia, Mexico, Netherlands, Russia, Spain, Turkey (Türkiye)
Participant flow
Recruitment details
A Phase IIb/III randomised, controlled, open-label, sequential, parallel-group, operationally seamless adaptive study with two parts. Part 1 was a Phase IIb proof-of-concept exploratory comparison of two groups each receiving a different dose of alteplase plus Standard of Care (SOC) versus a group receiving SOC alone. Part 2 was a confirmatory Phase III study; Part 2 will include one group receiving the selected dose of alteplase plus SOC vs. one group receiving SOC alone.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Alteplase Low Dose 0.3 milligram/kilogram (mg/kg) over 2 hours (Day 1) immediately followed by daily infusion of 0.02 mg/kg/hour over 12 hours (starting on Day 1 and up to Day 5), plus Standard of Care (SOC). One optional additional infusion of 0.3 mg/kg over 2 hours could be given once on Days 2 to 5 in case of clinical worsening, per investigator judgement. Part 1 subjects were randomized equally (1:1:1) across the three Part 1 arms. | 20 |
| Part 1: Alteplase High Dose 0.6 milligram/kilogram (mg/kg) over 2 hours (Day 1) immediately followed by daily infusion of 0.04 mg/kg/hour over 12 hours (starting on Day 1 and up to Day 5), plus Standard of Care (SOC). One optional additional infusion of 0.6 mg/kg over 2 hours could be given once on Days 2 to 5 in case of clinical worsening, per investigator judgement. Part 1 subjects were randomized equally (1:1:1) across the three Part 1 arms. | 20 |
| Part 1: Standard of Care Standard of Care included best possible treatment regimen established locally and was in line with current guidelines for Acute respiratory distress syndrome treatment. Part 1 subjects were randomized equally (1:1:1) across the three Part 1 arms. | 22 |
| Part 2: Alteplase High Dose - Non-invasive Mechanical Ventilation (NIV) Patients 0.6 milligram/kilogram (mg/kg) over 2 hours (Day 1) immediately followed by daily infusion of 0.04 mg/kg/hour over 12 hours (starting on Day 1 and up to Day 5), plus Standard of Care (SOC). One optional additional infusion of 0.6 mg/kg over 2 hours could be given once on Days 2 to 5 in case of clinical worsening, per investigator judgement. Non-invasive mechanical ventilation (NIV) patients are those with a baseline World Health Organization (WHO) Clinical Progression Scale value of 6. Part 2 subjects were randomized 2 (Alteplase) to 1 (SOC). | 17 |
| Part 2: Standard of Care - Non-invasive Mechanical Ventilation (NIV) Patients Standard of Care included best possible treatment regimen established locally and was in line with current guidelines for Acute respiratory distress syndrome treatment. Non-invasive mechanical ventilation (NIV) patients are those with a baseline World Health Organization (WHO) Clinical Progression Scale value of 6. Part 2 subjects were randomized 2 (Alteplase) to 1 (SOC). | 8 |
| Part 2: Alteplase High Dose - Invasive Mechanical Ventilation (IMV) Patients 0.6 milligram/kilogram (mg/kg) over 2 hours (Day 1) immediately followed by daily infusion of 0.04 mg/kg/hour over 12 hours (starting on Day 1 and up to Day 5), plus Standard of Care (SOC). One optional additional infusion of 0.6 mg/kg over 2 hours could be given once on Days 2 to 5 in case of clinical worsening, per investigator judgement. Invasive mechanical ventilation (IMV) patients are those with a baseline World Health Organization (WHO) Clinical Progression Scale value of 7, 8 or 9. Part 2 subjects were randomized 2 (Alteplase) to 1 (SOC). | 12 |
| Part 2: Standard of Care - Invasive Mechanical Ventilation (IMV) Patients Standard of Care included best possible treatment regimen established locally and was in line with current guidelines for Acute respiratory distress syndrome treatment. Invasive mechanical ventilation (IMV) patients are those with a baseline World Health Organization (WHO) Clinical Progression Scale value of 7, 8 or 9. Part 2 subjects were randomized 2 (Alteplase) to 1 (SOC). | 5 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 7 | 0 | 5 | 0 | 4 | 0 |
| Overall Study | fibrinogen level too low | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | mild bleeding | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | pO2/FIO2 ratio too high | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Transferred from Intensive Care Unit to Hospital Ward | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1: Alteplase Low Dose | Part 1: Alteplase High Dose | Part 1: Standard of Care | Part 2: Alteplase High Dose - Non-invasive Mechanical Ventilation (NIV) Patients | Part 2: Standard of Care - Non-invasive Mechanical Ventilation (NIV) Patients | Part 2: Alteplase High Dose - Invasive Mechanical Ventilation (IMV) Patients | Part 2: Standard of Care - Invasive Mechanical Ventilation (IMV) Patients | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 61.0 years STANDARD_DEVIATION 12 | 61.6 years STANDARD_DEVIATION 9.8 | 60.3 years STANDARD_DEVIATION 13 | 63.4 years STANDARD_DEVIATION 11.5 | 60.5 years STANDARD_DEVIATION 10.9 | 59.7 years STANDARD_DEVIATION 11.1 | 67.6 years STANDARD_DEVIATION 10.5 | 61.5 years STANDARD_DEVIATION 11.3 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native & White | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Missing | 7 Participants | 7 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 4 Participants | 38 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander & White | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 13 Participants | 13 Participants | 14 Participants | 10 Participants | 3 Participants | 7 Participants | 1 Participants | 61 Participants |
| Sex: Female, Male Female | 10 Participants | 3 Participants | 9 Participants | 3 Participants | 5 Participants | 1 Participants | 1 Participants | 32 Participants |
| Sex: Female, Male Male | 10 Participants | 17 Participants | 13 Participants | 14 Participants | 3 Participants | 11 Participants | 4 Participants | 72 Participants |
| WHO Clinical Progression Scale 0 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| WHO Clinical Progression Scale 1 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| WHO Clinical Progression Scale 10 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| WHO Clinical Progression Scale 2 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| WHO Clinical Progression Scale 3 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| WHO Clinical Progression Scale 4 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| WHO Clinical Progression Scale 5 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| WHO Clinical Progression Scale 6 | 16 Participants | 16 Participants | 16 Participants | 17 Participants | 8 Participants | 0 Participants | 0 Participants | 73 Participants |
| WHO Clinical Progression Scale 7 | 1 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 9 Participants |
| WHO Clinical Progression Scale 8 | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 8 Participants | 0 Participants | 11 Participants |
| WHO Clinical Progression Scale 9 | 1 Participants | 3 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants | 2 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 20 | 6 / 20 | 9 / 22 | 2 / 17 | 3 / 8 | 3 / 12 | 2 / 5 |
| other Total, other adverse events | 11 / 20 | 11 / 20 | 12 / 22 | 12 / 17 | 4 / 8 | 11 / 12 | 5 / 5 |
| serious Total, serious adverse events | 8 / 20 | 10 / 20 | 12 / 22 | 7 / 17 | 4 / 8 | 9 / 12 | 2 / 5 |
Outcome results
Primary
Time to Clinical Improvement or Hospital Discharge up to Day 28
From randomisation to either an improvement of 2 points on the 11-point World Health Organization (WHO) Clinical Progression Scale (from 0 to 10, a low score indicates a better outcome) or discharge from the hospital, whichever comes first. Full scale: 0=Uninfected; no viral RNA detected 1. Asymptomatic; viral RNA detected 2. Symptomatic; independent 3. Symptomatic; assistance needed 4. Hospitalised; no oxygen therapy 5. Hospitalised; oxygen by mask or nasal prongs 6. Hospitalised; oxygen by NIV or high flow 7. Intubation and mechanical ventilation, PaO2/FiO2=150 or SpO2/FiO2=200 8. Mechanical ventilation PaO2/FiO2\<150 (SpO2/FiO2\<200) or vasopressors 9. Mechanical ventilation PaO2/FiO2\<150 and vasopressors, dialysis, or ECMO 10. Dead Patients that have not met the endpoint were censored at Day 28 if they died prior to Day 28. Patients receiving bail out therapy without having first met the endpoint, were censored on the day of bail-out (hypothetical estimand).
Time frame: Up to 28 days.
Population: Full Analysis Set (FAS) consisted of all randomised patients with at least one baseline and one post baseline assessment relating to the primary endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Alteplase Low Dose | Time to Clinical Improvement or Hospital Discharge up to Day 28 | NA days |
| Part 1: Alteplase High Dose | Time to Clinical Improvement or Hospital Discharge up to Day 28 | 19.0 days |
| Part 1: Standard of Care | Time to Clinical Improvement or Hospital Discharge up to Day 28 | NA days |
| Part 2: Alteplase High Dose - Non-invasive Mechanical Ventilation (NIV) Patients | Time to Clinical Improvement or Hospital Discharge up to Day 28 | 22.0 days |
| Part 2: Standard of Care - Non-invasive Mechanical Ventilation (NIV) Patients | Time to Clinical Improvement or Hospital Discharge up to Day 28 | NA days |
| Part 2: Alteplase High Dose - Invasive Mechanical Ventilation (IMV) Patients | Time to Clinical Improvement or Hospital Discharge up to Day 28 | 25.5 days |
| Part 2: Standard of Care - Invasive Mechanical Ventilation (IMV) Patients | Time to Clinical Improvement or Hospital Discharge up to Day 28 | NA days |
Comparison: Unadjusted Hazard Ratio: Cox proportional hazard model containing fixed effect for treatment. The confidence intervals was determined using the Wald method to determine the variance.95% CI: [0.39, 2.61]
Comparison: Adjusted Hazard Ratio: Cox proportional hazard model containing fixed effect for treatment,ventilation status at baseline and age. The confidence intervals was determined using the Wald method to determine the variance.95% CI: [0.46, 3.27]
Comparison: Unadjusted Hazard Ratio: Cox proportional hazard model containing fixed effect for treatment. The confidence intervals was determined using the Wald method to determine the variance.95% CI: [0.73, 4.15]
Comparison: Adjusted Hazard Ratio: Cox proportional hazard model containing fixed effect for treatment,ventilation status at baseline and age. The confidence intervals was determined using the Wald method to determine the variance.95% CI: [0.83, 5.01]
Comparison: Unadjusted Hazard Ratio: Cox proportional hazard model containing fixed effect for treatment. The confidence intervals was determined using the Wald method to determine the variance.95% CI: [0.35, 3.66]
Comparison: Adjusted Hazard Ratio: Cox proportional hazard model containing fixed effect for treatment,ventilation status at baseline and age. The confidence intervals was determined using the Wald method to determine the variance.95% CI: [0.33, 4.22]
Secondary
All Cause Mortality at Day 28
All cause mortality at Day 28. If it is unknown whether the patient was dead at end of Day 28, then it will be assumed that the patient did not die up to Day 28, regardless of the reason. This unfavorable endpoint is met if: * the last known status of the patient is 10 on the WHO clinical progression scale by the end of Day 28, or * vital status is dead within 28 days
Time frame: Up to 28 days.
Population: Full Analysis Set (FAS) consisted of all randomised patients with at least one baseline and one post baseline assessment relating to the primary endpoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Alteplase Low Dose | All Cause Mortality at Day 28 | 2 Participants |
| Part 1: Alteplase High Dose | All Cause Mortality at Day 28 | 3 Participants |
| Part 1: Standard of Care | All Cause Mortality at Day 28 | 6 Participants |
| Part 2: Alteplase High Dose - Non-invasive Mechanical Ventilation (NIV) Patients | All Cause Mortality at Day 28 | 1 Participants |
| Part 2: Standard of Care - Non-invasive Mechanical Ventilation (NIV) Patients | All Cause Mortality at Day 28 | 2 Participants |
| Part 2: Alteplase High Dose - Invasive Mechanical Ventilation (IMV) Patients | All Cause Mortality at Day 28 | 2 Participants |
| Part 2: Standard of Care - Invasive Mechanical Ventilation (IMV) Patients | All Cause Mortality at Day 28 | 2 Participants |
Comparison: Adjusted risk difference and 95% confidence interval is based upon average marginal effect Delta method, adjusting for baseline ventilation status, age and treatment.95% CI: [-38.6, 5.5]
Comparison: Adjusted risk difference and 95% confidence interval is based upon average marginal effect Delta method, adjusting for baseline ventilation status, age and treatment.95% CI: [-35.1, 11.6]
Comparison: Unadjusted risk difference and 95% CI is based upon average marginal effect Delta method, adjusting for treatment.p-value: 0.241995% CI: [-51.1, 12.9]The delta method and average marginal.
Secondary
Daily Average PaO2/FiO2 Ratio Change From Baseline to Day 6
Daily average PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change from baseline to Day 6. This assessment was measured approximately 3-times daily. All available values on each of these days, regardless of the position of the patient when being measured, were averaged in order to determine the daily average PaO2/FiO2 ratio for that patient. The higher the value the better the health status of the patient. If the patient was still in hospital during day 6 then the day 6 daily average value was used, if available. If the patient was discharged from hospital prior to day 6 then the daily average at the time of hospital discharge was used as a surrogate for day 6, if available. If the patient died prior to day 6 then there was no imputation but the death handled as failure in the determination of the difference in medians and 95% CI. Based upon this, the change from baseline for each patient was calculated.
Time frame: Up to 6 days.
Population: Full Analysis Set (FAS) consisted of all randomised patients with at least one baseline and one post baseline assessment relating to the primary endpoint. Only subjects with non-missing endpoint data were included. The endpoint was only planned for subjects in Part 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Alteplase Low Dose | Daily Average PaO2/FiO2 Ratio Change From Baseline to Day 6 | 32.2 PaO2/FiO2 ratio |
| Part 1: Alteplase High Dose | Daily Average PaO2/FiO2 Ratio Change From Baseline to Day 6 | 58.5 PaO2/FiO2 ratio |
| Part 1: Standard of Care | Daily Average PaO2/FiO2 Ratio Change From Baseline to Day 6 | 7.5 PaO2/FiO2 ratio |
Comparison: Based upon Hedges-Lehmann estimator handling deaths as failure and Wilcoxon rank sum test methodology.95% CI: [-28.45, 52.33]
Comparison: Based upon Hedges-Lehmann estimator handling deaths as failure and Wilcoxon rank sum test methodology.95% CI: [0.49, 110.36]
Secondary
Length of Hospital Stay up to Day 28
Length of hospital stay up to day 28 was determined based upon the first hospital discharge date, or discharge to another care facility. If the patient died within the first 28 day period, then length of hospital stay was 28.
Time frame: Up to 28 days.
Population: Full Analysis Set (FAS) consisted of all randomised patients with at least one baseline and one post baseline assessment relating to the primary endpoint. The endpoint was only planned for subjects in Part 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Alteplase Low Dose | Length of Hospital Stay up to Day 28 | 28.0 Days |
| Part 1: Alteplase High Dose | Length of Hospital Stay up to Day 28 | 24.0 Days |
| Part 1: Standard of Care | Length of Hospital Stay up to Day 28 | 28.0 Days |
| Part 2: Alteplase High Dose - Non-invasive Mechanical Ventilation (NIV) Patients | Length of Hospital Stay up to Day 28 | 28.0 Days |
Comparison: Unadjusted mean difference: A restricted maximum likelihood (REML) based Analysis of Covariance (ANCOVA) was used. Adjustment was made for treatment.p-value: 0.985695% CI: [-7.5, 7.6]ANCOVA
Comparison: Adjusted mean difference: A restricted maximum likelihood (REML) based Analysis of Covariance (ANCOVA) was used. Adjustment was made for treatment, the number of days under NIV support, baseline D-Dimer level and age.p-value: 0.872995% CI: [-8.5, 7.3]ANCOVA
Secondary
Number of Oxygen-free Days up to Day 28
Number of oxygen-free days (OFD) up to Day 28. Oxygen-free is defined as free from assistance from oxygen support. The number of oxygen-free days starts from when the patient has a 'lasting' value on the WHO clinical progression scale of ≤ 4 and ends on Day 28. A lasting value of ≤ 4 means that the value cannot exceed 4 at a later timepoint. If the patient is liberated from oxygen on Day x, then the number of OFDs is 28-x. If a patient has withdrawn consent prior to day 28 then he will have a missing value for OFD. In any case, if the status of the patient at Day 28 is death, as determined from the vital status page then the OFD=0.
Time frame: Up to 28 days.
Population: Full Analysis Set (FAS) consisted of all randomised patients with at least one baseline and one post baseline assessment relating to the primary endpoint. The endpoint was only planned for subjects in Part 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Alteplase Low Dose | Number of Oxygen-free Days up to Day 28 | 7.0 Days |
| Part 1: Alteplase High Dose | Number of Oxygen-free Days up to Day 28 | 4.5 Days |
| Part 1: Standard of Care | Number of Oxygen-free Days up to Day 28 | 0.0 Days |
| Part 2: Alteplase High Dose - Non-invasive Mechanical Ventilation (NIV) Patients | Number of Oxygen-free Days up to Day 28 | 0.0 Days |
Secondary
Number of Subjects With Improvement of Sequential (Sepsis-related) Organ Failure Assessment (SOFA) Score by ≥2 Points at Day 6
Number of subjects with improvement of Sequential (sepsis-related) Organ Failure Assessment (SOFA) score by ≥2 points from baseline to end of Day 6. The Sequential Organ Failure Assessment (SOFA) scores six variables: respiratory, coagulation, liver, Cardiovascular, central nervous system and renal. Each variable is score from 0 (best outcome) to 4 (worst outcome) with a total score calculated as the sum of all six variables ranging from 0 (best outcome) to 24 (worst outcome).
Time frame: Baseline (Day 0) and Day 6 of treatment
Population: Full Analysis Set (FAS) consisted of all randomised patients with at least one baseline and one post baseline assessment relating to the primary endpoint. The endpoint was only planned for subjects in Part 1.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Alteplase Low Dose | Number of Subjects With Improvement of Sequential (Sepsis-related) Organ Failure Assessment (SOFA) Score by ≥2 Points at Day 6 | 4 Participants |
| Part 1: Alteplase High Dose | Number of Subjects With Improvement of Sequential (Sepsis-related) Organ Failure Assessment (SOFA) Score by ≥2 Points at Day 6 | 2 Participants |
| Part 1: Standard of Care | Number of Subjects With Improvement of Sequential (Sepsis-related) Organ Failure Assessment (SOFA) Score by ≥2 Points at Day 6 | 6 Participants |
Comparison: Adjusted risk difference and 95% confidence interval is based upon average marginal effect Delta method, adjusting for baseline ventilation status, age and treatment.95% CI: [-29, 19.2]
Comparison: Adjusted risk difference and 95% confidence interval is based upon average marginal effect Delta method, adjusting for baseline ventilation status, age and treatment.95% CI: [-36.8, 6.3]
Secondary
Number of Subjects With Major Bleeding Events (MBE) at Day 6
Number of subjects with major bleeding events (MBE). Major bleeding events (MBE) according to International Society on Thrombosis and Haemostasis \[ISTH\] definition until Day 6. Definition of a major bleed: •Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or •Bleeding associated with a reduction in hemoglobin of at least 2 gram/deciliter (1.24 millimole/Liter), or leading to transfusion of two or more units of blood or packed cells and/or •Fatal bleed
Time frame: From start of treatment (Alteplase) or randomisation (SOC) (day 1) till Day 6, up to 6 days.
Population: The Treated Set (TS) consisted of all patients who were randomised and, for patients in the alteplase groups, treated with at least one dose of trial drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Alteplase Low Dose | Number of Subjects With Major Bleeding Events (MBE) at Day 6 | 1 Participants |
| Part 1: Alteplase High Dose | Number of Subjects With Major Bleeding Events (MBE) at Day 6 | 4 Participants |
| Part 1: Standard of Care | Number of Subjects With Major Bleeding Events (MBE) at Day 6 | 0 Participants |
| Part 2: Alteplase High Dose - Non-invasive Mechanical Ventilation (NIV) Patients | Number of Subjects With Major Bleeding Events (MBE) at Day 6 | 2 Participants |
| Part 2: Standard of Care - Non-invasive Mechanical Ventilation (NIV) Patients | Number of Subjects With Major Bleeding Events (MBE) at Day 6 | 0 Participants |
| Part 2: Alteplase High Dose - Invasive Mechanical Ventilation (IMV) Patients | Number of Subjects With Major Bleeding Events (MBE) at Day 6 | 2 Participants |
| Part 2: Standard of Care - Invasive Mechanical Ventilation (IMV) Patients | Number of Subjects With Major Bleeding Events (MBE) at Day 6 | 0 Participants |
95% CI: [-10.892, 24.8734]
95% CI: [2.3075, 43.6615]
95% CI: [-24.127, 36.9012]
Secondary
Number of Subjects With Treatment Failure at Day 28
Treatment failure defined as all cause mortality or mechanical ventilation at Day 28.
Time frame: Up to 28 days.
Population: Full Analysis Set (FAS) consisted of all randomised patients with at least one baseline and one post baseline assessment relating to the primary endpoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Alteplase Low Dose | Number of Subjects With Treatment Failure at Day 28 | 8 Participants |
| Part 1: Alteplase High Dose | Number of Subjects With Treatment Failure at Day 28 | 8 Participants |
| Part 1: Standard of Care | Number of Subjects With Treatment Failure at Day 28 | 11 Participants |
| Part 2: Alteplase High Dose - Non-invasive Mechanical Ventilation (NIV) Patients | Number of Subjects With Treatment Failure at Day 28 | 6 Participants |
| Part 2: Standard of Care - Non-invasive Mechanical Ventilation (NIV) Patients | Number of Subjects With Treatment Failure at Day 28 | 3 Participants |
| Part 2: Alteplase High Dose - Invasive Mechanical Ventilation (IMV) Patients | Number of Subjects With Treatment Failure at Day 28 | 5 Participants |
| Part 2: Standard of Care - Invasive Mechanical Ventilation (IMV) Patients | Number of Subjects With Treatment Failure at Day 28 | 3 Participants |
Comparison: Adjusted risk difference and 95% confidence interval is based upon average marginal effect Delta method, adjusting for baseline ventilation status, age and treatment.95% CI: [-37.1, 19.1]
Comparison: Adjusted risk difference and 95% confidence interval is based upon average marginal effect Delta method, adjusting for baseline ventilation status, age and treatment.95% CI: [-37.2, 19]
Comparison: Adjusted risk difference and 95% CI is based upon average marginal effect Delta method, adjusting for baseline D-dimer status, age, days of NIV support and treatment.p-value: 0.252395% CI: [-10.3, 39.3]The delta method and average marginal.
Secondary
Number of Ventilator-free Days at Day 28
Number of ventilator-free days (VFDs) from start of treatment to Day 28. 'Ventilator' is defined as 'assisted breathing' but it refers to mechanical invasive ventilation. The number of VFDs starts from when the patient has a 'lasting' value on the WHO clinical progression scale of ≤ 6, and ends on Day 28. A lasting value of ≤ 6 means that the value cannot exceed 6 at a later timepoint. If the patient is liberated from the ventilator on Day x, then the number of VFDs is 28-x. If a patient has withdrawn consent prior to day 28 then he will have a missing value for VFD. In any case, if the status of the patient at Day 28 is death, as determined from the vital status page then the VFD=0.
Time frame: Up to 28 days.
Population: Full Analysis Set (FAS) consisted of all randomised patients with at least one baseline and one post baseline assessment relating to the primary endpoint. The endpoint was only planned for subjects in Part 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Alteplase Low Dose | Number of Ventilator-free Days at Day 28 | 10.6 Days | Standard Error 2.9 |
| Part 1: Alteplase High Dose | Number of Ventilator-free Days at Day 28 | 11.8 Days | Standard Error 2.9 |
| Part 1: Standard of Care | Number of Ventilator-free Days at Day 28 | 7.5 Days | Standard Error 2.7 |
Comparison: Parameters included in model: treatment,ventilation status at baseline, and age.95% CI: [-4.4, 10.6]
Comparison: Parameters included in model: treatment,ventilation status at baseline, and age.95% CI: [-3.2, 11.8]
Secondary
Worst PaO2/FiO2 Ratio Change From Baseline to Day 6
Worst PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change from baseline to day 6. This assessment was planned to be measured on each of days 0 to 6. but only whilst the patients was still in hospital. The worst (lowest) daily measurement will be used and the higher the value the better the health status of the patient. * If the patient was still in hospital during day 6 then the day 6 value was used * If the patient was discharged from hospital prior to day 6 then the value at the time of hospital discharge was used * If the patient died prior to day 6 then the last value prior to death was used * If day 6 value was missing but Day 5 value available, the day 5 value was used * If day 6 value was missing, no Day 5 value available, but day 7 available, then day 7 value was used * Otherwise value was set to missing for that patient. Based upon this, the change from baseline for each patient was calculated and used for the analysis.
Time frame: Up to 7 days.
Population: Full Analysis Set (FAS) consisted of all randomised patients with at least one baseline and one post baseline assessment relating to the primary endpoint. The endpoint was only planned for subjects in Part 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Alteplase Low Dose | Worst PaO2/FiO2 Ratio Change From Baseline to Day 6 | 70.8 PaO2/FiO2 ratio | Standard Error 20.7 |
| Part 1: Alteplase High Dose | Worst PaO2/FiO2 Ratio Change From Baseline to Day 6 | 0.0 PaO2/FiO2 ratio | Standard Error 29.2 |
| Part 1: Standard of Care | Worst PaO2/FiO2 Ratio Change From Baseline to Day 6 | -10.9 PaO2/FiO2 ratio | Standard Error 13.1 |
| Part 2: Alteplase High Dose - Non-invasive Mechanical Ventilation (NIV) Patients | Worst PaO2/FiO2 Ratio Change From Baseline to Day 6 | 3.4 PaO2/FiO2 ratio | Standard Error 20.2 |
Comparison: Unadjusted mean difference: A restricted maximum likelihood (REML) based Analysis of Covariance (ANCOVA) was used. Adjustment was made for treatment.p-value: 0.060395% CI: [-3.3, 145.1]ANCOVA
Comparison: Adjusted mean difference: A restricted maximum likelihood (REML) based Analysis of Covariance (ANCOVA) was used. Adjustment was made for treatment, the number of days under NIV support, baseline D-Dimer level, baseline PaO2/FiO2 ratio and age.p-value: 0.036295% CI: [6.3, 168]ANCOVA