The TRISTARDS trial - ThRombolysIS Therapy for ARDS A study to test whether different doses of alteplase help people with severe breathing problems because of COVID 19.

Phase 1

Conditions: Acute respiratory distress syndrome caused by Covid-19
MedDRA version: 21.1Level: PTClassification code 10001052Term: Acute respiratory distress syndromeSystem Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

Registration Number: EUCTR2020-002913-16-FR

Lead Sponsor: Boehringer Ingelheim France

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 270

Inclusion Criteria

1.Age = 18 years (or above legal age, e.g. UK =16 years)
2.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)
3.SARS-CoV-2 positive (laboratory-confirmed RT-PCR test)
4.Fibrinogen level = upper limit of normal
5.D-Dimer = 3-fold of upper limit of normal (ULN) according to local laboratory
6.Signed and dated written informed consent in accordance with ICH Good Clinical Practice (GCP) and local legislation prior to admission to the trial.

Are the trial subjects under 18? yes
Number of subjects for this age range: 10
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 90
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 178

Exclusion Criteria

1.Massive confirmed pulmonary embolism (PE) with haemodynamic instability at trial entry
2.Patients on mechanical ventilation for longer than 48 hours
3.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
4.Has a Do-Not-Intubate (DNI) or Do-Not-Resuscitate (DNR) order
5.In the opinion of the investigator, is not expected to survive for
> 48 hours after admission
6.Patients with known hypersensitivity to the active substance alteplase, gentamicin (a trace residue from the manufacturing process) or to any of the excipients
7.Significant bleeding disorder at present or within the past 3 months, known haemorrhagic diathesis
8.Patients receiving effective oral anticoagulant treatment, e.g. vitamin K antagonists with INR >1.3, or any direct oral anticoagulant within the past 48 hours
9.Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery)
10.History or evidence or suspicion of intracranial haemorrhage including sub-arachnoid haemorrhage
11.Severe uncontrolled arterial hypertension (according to the investigator`s judgement)
12.Major surgery or significant trauma in the past 10 days, recent trauma to head or cranium
13.Cardiac arrest and/or cardiopulmonary resuscitation during the current hospital stay
14.Obstetrical delivery within the past 10 days
15.Severe hepatic dysfunction, including biopsy confirmed hepatic cirrhosis, portal hypertension, hepatic encephalopathy, or active hepatitis
16.Bacterial endocarditis, pericarditis
17.Acute pancreatitis
18.Documented ulcerative gastro-intestinal disease during the last 3 months
19.Severe heart failure (New York Heart Association Class IV)
20.Arterial aneurysms, arterial/venous malformations
21.Malignancy (Stage IV)
22.Haemorrhagic stroke or stroke of unknown origin at any time
23.Ischaemic stroke or transient ischaemic attack (TIA) in the preceding 6 months

Further criteria apply.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the efficacy and safety of intravenous alteplase in ARDS triggered by COVID-19.;Secondary Objective: Not applicable;Primary end point(s): 1) Time to clinical improvement or hospital discharge up to Day 28, defined as the time from randomization to either an improvement of two points on the 11-point WHO Clinical Progression Scale or discharge from the hospital, whichever comes first. ;Timepoint(s) of evaluation of this end point: 1) up to day 28

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1) All cause mortality at Day 28<br>2) Number of ventilator-free days from start of treatment to Day 28<br>3) Improvement of Sequential (sepsis-related) Organ Failure Assessment (SOFA) score by =2 points from baseline to end of Day 6 <br>4) Major bleeding events (MBE) (according to International Society on Thrombosis and Haemostasis [ISTH] definition until Day 6<br>5) Daily average PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change from baseline to Day 6<br>6) All-cause mortality or on mechanical ventilation at Day 28<br>;Timepoint(s) of evaluation of this end point: 1) Day 28<br>2) Day 28<br>3) Day 6<br>4) Day 6<br>5) Day 6<br>5) Day 28<br>

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