A Study to Test Whether Different Doses of Alteplase Help People With Severe Breathing Problems Because of COVID-19

Study Overview
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Brief Summary
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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.

Official Title
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The TRISTARDS Trial - ThRombolysIS Therapy for ARDS A Phase IIb/III Operationally Seamless, Open-label, Randomised, Sequential, Parallel-group Adaptive Study to Evaluate the Efficacy and Safety of Daily Intravenous Alteplase Treatment Given up to 5 Days on Top of Standard of Care (SOC) Compared With SOC Alone, in Patients With Acute Respiratory Distress Syndrome (ARDS) Triggered by COVID-19

Conditions
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Acute Respiratory Distress Syndrome

Intervention / Treatment
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* Drug: Alteplase
* Procedure: Standard of care


Participation Criteria
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Eligibility Criteria
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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 exclusion criteria apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study comprises two parts: Part 1 (dose-finding, Phase IIb) and Part 2 (confirmatory, Phase III)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Control group<br>Standard of care alone | Procedure: Standard of care<br>* 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.<br>|
| Experimental: Treatment group A<br>Alteplase (low dose) on top of standard of care | Drug: Alteplase<br>* Alteplase<br>Procedure: Standard of care<br>* 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.<br>|
| Experimental: Treatment group B<br>Alteplase (high dose) on top of standard of care | Drug: Alteplase<br>* Alteplase<br>Procedure: Standard of care<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to clinical improvement or hospital discharge | Time from randomisation to either an improvement of two points on the 11-point WHO Clinical Progression Scale or discharge from the hospital, whichever comes first. The WHO Clinical Progression Scale ranges from 0 to 10. A higher score indicates a worsening of the patient status. | Up to day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All cause mortality |  | At day 28 | 
| Number of ventilator-free days |  | From start of treatment to day 28 | 
| Improvement of Sequential (sepsis-related) Organ Failure Assessment (SOFA) score by ≥2 points | The SOFA score ranges from 0 to 6. A higher score indicates a worsening of the symptoms. | From baseline to end of day 6 | 
| Number of major bleeding events (MBE) | according to International Society on Thrombosis and Haemostasis (ISTH) definition | Up to day 6 | 
| Daily average PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change | PaO2: partial oxygen pressure in arterial blood FiO2: fraction of inspired oxygen SpO2: Oxygen saturation | From baseline to end of day 6 | 
| All-cause mortality or on mechanical ventilation |  | At day 28 | 
| Treatment failure | part 2: defined as all cause mortality or mechanical ventilation | At Day 28 | 
| All cause mortality | part 2 | At Day 28 | 
| Number of oxygen-free days | part 2 | Up to Day 28 | 
| Length of hospital stay | part 2 | Up to Day 28 | 
| Major bleeding events (MBE) | part 2 | Up to Day 6 | 
| PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change | part 2: PaO2: partial oxygen pressure in arterial blood FiO2: fraction of inspired oxygen SpO2: Oxygen saturation | From baseline to end of Day 6 |