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

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

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.

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.