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

Boehringer Ingelheim

Status and phase: Completed; Phase 3; Phase 2

Conditions: Acute Respiratory Distress Syndrome

Treatments: Drug: Alteplase low dose; Drug: Alteplase high dose; Procedure: Standard of care

Study type: Interventional

Funder types: Industry

Identifiers

NCT04640194

2020-002913-16 (EudraCT Number)

0135-0347

Details and patient eligibility

About

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.

Enrollment: 104 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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104 participants in 7 patient groups

Part 1: Alteplase low dose

Experimental group

Description:

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.

Treatment:

Procedure: Standard of care

Drug: Alteplase low dose

Part 1: Alteplase high dose

Experimental group

Description:

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.

Treatment:

Procedure: Standard of care

Drug: Alteplase high dose

Part 1: Standard of Care

Other group

Description:

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.

Treatment:

Procedure: Standard of care

Part 2: Alteplase high dose - non-invasive mechanical ventilation (NIV) patients

Experimental group

Description:

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).

Treatment:

Procedure: Standard of care

Drug: Alteplase high dose

Part 2: Standard of Care - non-invasive mechanical ventilation (NIV) patients

Other group

Description:

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).

Treatment:

Procedure: Standard of care

Part 2: Alteplase high dose - invasive mechanical ventilation (IMV) patients

Experimental group

Description:

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).

Treatment:

Procedure: Standard of care

Drug: Alteplase high dose

Part 2: Standard of Care - invasive mechanical ventilation (IMV) patients

Other group

Description:

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).

Treatment:

Procedure: Standard of care