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

NCT ID: NCT04640194

Last Updated: 2024-03-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 104 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-12-16
• Study Completion Date: 2022-07-25

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.

Conditions

Acute Respiratory Distress Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Standard of care

Intervention Type: PROCEDURE

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.

Alteplase low dose

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

Standard of care

Intervention Type: PROCEDURE

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.

Alteplase high dose

Intervention Type: DRUG

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.

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.

Group Type: OTHER

Standard of care

Intervention Type: PROCEDURE

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.

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).

Group Type: EXPERIMENTAL

Standard of care

Intervention Type: PROCEDURE

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.

Alteplase high dose

Intervention Type: DRUG

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.

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).

Group Type: OTHER

Standard of care

Intervention Type: PROCEDURE

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.

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).

Group Type: EXPERIMENTAL

Standard of care

Intervention Type: PROCEDURE

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.

Alteplase high dose

Intervention Type: DRUG

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.

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).

Group Type: OTHER

Standard of care

Intervention Type: PROCEDURE

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.

Interventions

Standard 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.

Intervention Type: PROCEDURE

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). 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.

Intervention Type: DRUG

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). 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.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Boehringer Ingelheim

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

LKH Klagenfurt am Woerthersee

Klagenfurt, , Austria

Wiener Gesundheitsverbund Klinik Favoriten

Vienna, , Austria

ULB Hopital Erasme

Brussels, , Belgium

Centre Hospitalier Universitaire de Liège

Liège, , Belgium

Ottignies - HOSP St-Pierre

Ottignies, , Belgium

Hospital Mae de Deus

Porto Alegre, , Brazil

HOP Bicêtre

Le Kremlin-Bicêtre, , France

HOP Roger Salengro

Lille, , France

HOP Melun-Sénart

Melun, , France

HOP Hôtel-Dieu

Nantes, , France

HOP Cochin

Paris, , France

HOP Européen G. Pompidou

Paris, , France

HOP Robert Debré

Reims, , France

HOP Civil

Strasbourg, , France

Medizinische Hochschule Hannover

Hanover, , Germany

Universitätsklinikum Heidelberg

Heidelberg, , Germany

Universitätsklinikum Leipzig

Leipzig, , Germany

Universitätsklinikum Mannheim GmbH

Mannheim, , Germany

Klinikum der Universität München - Campus Großhadern

München, , Germany

Petrus-Krankenhaus

Wuppertal, , Germany

King George Hospital

Visakhapatnam, , India

IRCCS San Raffaele

Milan, , Italy

Istituto Clinico Humanitas

Rozzano (MI), , Italy

Hospital Miri

Miri, , Malaysia

Hospital Cardiologica Aguascalientes

Aguascalientes, , Mexico

Gelre Ziekenhuizen Apeldoorn

Apeldoorn, , Netherlands

Rijnstate Hospital

Arnhem, , Netherlands

Canisius-Wilhelmina ziekenhuis

Nijmegen, , Netherlands

City Clinical Hospital # 40 of the Moscow Health Department

Moscow, , Russia

Moscow 1st State Med.Univ.n.a.I.M.Sechenov

Moscow, , Russia

City Clinical Emergency Hospital

Ryazan, , Russia

State Budget Institution of Healthcare Leningradskaya region "Kirovskaya Interdistrict Hospital"

Saint Petersburg, , Russia

Hospital del Mar

Barcelona, , Spain

Hospital Vall d'Hebron

Barcelona, , Spain

Hospital Puerta del Mar

Cadiz, , Spain

CS Parc Taulí

Sabadell, , Spain

Izmir Dr. Suat Seren Gogus Hastaliklari ve Cerrahisi Egitim ve Arastirma Hastanesi

Izmir, , Turkey (Türkiye)

Countries

Austria; Belgium; Brazil; France; Germany; India; Italy; Malaysia; Mexico; Netherlands; Russia; Spain; Turkey (Türkiye)

References

Landoni G, Chowdary P, Meziani F, Creteur J, De Schryver N, Motsch J, Henrichmoeller I, Pages A, Peter N, Danays T, Weigand MA; TRISTARDS Investigators. Alteplase in COVID-19 severe hypoxemic respiratory failure: the TRISTARDS multicenter randomized trial. Ann Intensive Care. 2024 Nov 10;14(1):170. doi: 10.1186/s13613-024-01386-z.

Reference Type: DERIVED

PMID: 39522090 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.mystudywindow.com/

Related Info

Other Identifiers

2020-002913-16

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

0135-0347

Identifier Type: -

Identifier Source: org_study_id