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

NCT04640194 | Completed Phase 2 Results DMC

• 2 other identifiers: 0135-03472020-002913-16
• Study Type: interventional
• Target: 104
• Locations: 13 countries
• Sites: 37

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

Outcome Measures

Primary Outcomes (1)

• Time to Clinical Improvement or Hospital Discharge up to Day 28

  From randomisation to either an improvement of 2 points on the 11-point World Health Organization (WHO) Clinical Progression Scale (from 0 to 10, a low score indicates a better outcome) or discharge from the hospital, whichever comes first. Full scale: 0=Uninfected; no viral RNA detected 1. Asymptomatic; viral RNA detected 2. Symptomatic; independent 3. Symptomatic; assistance needed 4. Hospitalised; no oxygen therapy 5. Hospitalised; oxygen by mask or nasal prongs 6. Hospitalised; oxygen by NIV or high flow 7. Intubation and mechanical ventilation, PaO2/FiO2=150 or SpO2/FiO2=200 8. Mechanical ventilation PaO2/FiO2\<150 (SpO2/FiO2\<200) or vasopressors 9. Mechanical ventilation PaO2/FiO2\<150 and vasopressors, dialysis, or ECMO 10. Dead Patients that have not met the endpoint were censored at Day 28 if they died prior to Day 28. Patients receiving bail out therapy without having first met the endpoint, were censored on the day of bail-out (hypothetical estimand).

  Up to 28 days.

Secondary Outcomes (9)

• Number of Subjects With Major Bleeding Events (MBE) at Day 6

  From start of treatment (Alteplase) or randomisation (SOC) (day 1) till Day 6, up to 6 days.

• All Cause Mortality at Day 28

  Up to 28 days.

• Number of Subjects With Treatment Failure at Day 28

  Up to 28 days.

• Number of Ventilator-free Days at Day 28

  Up to 28 days.

• Number of Subjects With Improvement of Sequential (Sepsis-related) Organ Failure Assessment (SOFA) Score by ≥2 Points at Day 6

  Baseline (Day 0) and Day 6 of treatment

Study Arms (7)

Part 1: Alteplase low dose

EXPERIMENTAL

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.

Procedure: Standard of care; Drug: Alteplase low dose

Part 1: Alteplase high dose

EXPERIMENTAL

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.

Procedure: Standard of care; Drug: Alteplase high dose

Part 1: Standard of Care

OTHER

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.

Procedure: Standard of care

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

EXPERIMENTAL

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).

Procedure: Standard of care; Drug: Alteplase high dose

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

OTHER

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).

Procedure: Standard of care

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

EXPERIMENTAL

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).

Procedure: Standard of care; Drug: Alteplase high dose

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

OTHER

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).

Procedure: Standard of care

Interventions

Standard of care 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 1: Alteplase high dose; Part 1: Alteplase low dose; Part 1: Standard of Care; Part 2: Alteplase high dose - invasive mechanical ventilation (IMV) patients; Part 2: Alteplase high dose - non-invasive mechanical ventilation (NIV) patients; Part 2: Standard of Care - invasive mechanical ventilation (IMV) patients; Part 2: Standard of Care - non-invasive mechanical ventilation (NIV) patients

Alteplase low dose 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 low dose

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Boehringer Ingelheim: lead

Study Sites (37)

LKH Klagenfurt am Woerthersee

Klagenfurt, 9020, Austria

Location

Wiener Gesundheitsverbund Klinik Favoriten

Vienna, 1100, Austria

Location

ULB Hopital Erasme

Brussels, 1070, Belgium

Location

Centre Hospitalier Universitaire de Liège

Liège, 4000, Belgium

Location

Ottignies - HOSP St-Pierre

Ottignies, 1340, Belgium

Location

Hospital Mae de Deus

Porto Alegre, 90470-340, Brazil

Location

HOP Bicêtre

Le Kremlin-Bicêtre, 94275, France

Location

HOP Roger Salengro

Lille, 59037, France

Location

HOP Melun-Sénart

Melun, 77000, France

Location

HOP Hôtel-Dieu

Nantes, 44093, France

Location

HOP Cochin

Paris, 75014, France

Location

HOP Européen G. Pompidou

Paris, 75908, France

Location

HOP Robert Debré

Reims, 51092, France

Location

HOP Civil

Strasbourg, 67091, France

Location

Medizinische Hochschule Hannover

Hanover, 30625, Germany

Location

Universitätsklinikum Heidelberg

Heidelberg, 69120, Germany

Location

Universitätsklinikum Leipzig

Leipzig, 04109, Germany

Location

Universitätsklinikum Mannheim GmbH

Mannheim, 68167, Germany

Location

Klinikum der Universität München - Campus Großhadern

München, 81377, Germany

Location

Petrus-Krankenhaus

Wuppertal, 42283, Germany

Location

King George Hospital

Visakhapatnam, 530002, India

Location

IRCCS San Raffaele

Milan, 20132, Italy

Location

Istituto Clinico Humanitas

Rozzano (MI), 20089, Italy

Location

Hospital Miri

Miri, 98000, Malaysia

Location

Hospital Cardiologica Aguascalientes

Aguascalientes, 20230, Mexico

Location

Gelre Ziekenhuizen Apeldoorn

Apeldoorn, 7334 DZ, Netherlands

Location

Rijnstate Hospital

Arnhem, 6815 AD, Netherlands

Location

Canisius-Wilhelmina ziekenhuis

Nijmegen, 6532 SZ, Netherlands

Location

City Clinical Hospital # 40 of the Moscow Health Department

Moscow, 108814, Russia

Location

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

Moscow, 119048, Russia

Location

City Clinical Emergency Hospital

Ryazan, 390026, Russia

Location

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

Saint Petersburg, 187342, Russia

Location

Hospital del Mar

Barcelona, 08003, Spain

Location

Hospital Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Puerta del Mar

Cadiz, 11009, Spain

Location

CS Parc Taulí

Sabadell, 08208, Spain

Location

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

Izmir, 35110, Turkey (Türkiye)

Location

Related Publications (1)

• 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.

  PMID: 39522090 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Respiratory Distress Syndrome

Interventions

Standard of Care; Tissue Plasminogen Activator

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Respiration Disorders

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation; Serine Endopeptidases; Endopeptidases; Peptide Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Serine Proteases; Plasminogen Activators; Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Biological Factors

Limitations and Caveats

Results for the invasive mechanical ventilation (IMV) patients were only analyzed descriptively due to insufficient enrolled patients. For the All-Cause Mortality endpoint, the non-invasive mechanical ventilation (NIV) arm did not have enough events to perform the adjusted statistical model, instead the unadjusted model is presented for this endpoint.

Results Point of Contact

• Title: Boehringer Ingelheim, Call Center
• Organization: Boehringer Ingelheim

clintriage.rdg@boehringer-ingelheim.com

1-800-243-0127

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: The study comprises two parts: Part 1 (dose-finding, Phase IIb) and Part 2 (confirmatory, Phase III)

Study Record Dates

• First Submitted: November 20, 2020
• First Posted: November 23, 2020
• Study Start: December 16, 2020
• Primary Completion: July 19, 2022
• Study Completion: July 25, 2022
• Last Updated: March 20, 2024
• Results First Posted: March 7, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: After all regulatory activities are completed in the US and EU for the product and indication, and after the primary manuscript has been accepted for publication.
• Access Criteria: For study documents - upon signing of a 'Document Sharing Agreement'. For study data - 1. after the submission and approval of the research proposal (checks will be performed by both the independent review panel and the sponsor, including checking that the planned analysis does not compete with sponsor's publication plan); 2. and upon signing of a 'Data Sharing Agreement'.

Locations

RU (4); TU (1); IT (2); BE (3); DE (6); MY (1); NL (3); BR (1); AU (2); IN (1); FR (8); ES (4); ME (1)