Acute Respiratory Distress SyndromePhase 2/3TRISTARDSNCT04640194
A Study to Test Whether Different Doses of Alteplase Help People With Severe Breathing Problems Because of COVID-19
A Phase 2/3 study testing Alteplase low dose and Alteplase high dose in people with Acute Respiratory Distress Syndrome, run by Boehringer Ingelheim at 37 sites in 13 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Respiratory Distress Syndrome
- What is being tested?
- Alteplase low dose and Alteplase high dose
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 104 participants
- Where
- 37 sitesin 13 countries
- Study dates
- 16 Dec 2020to 25 Jul 2022
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 10Show fewer
- 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 locations and contacts
37 sites in 13 countries.
37 sites in 13 countries
France8 sites
HOP Bicêtre
Le Kremlin-Bicêtre, 94275
HOP Roger Salengro
Lille, 59037
HOP Melun-Sénart
Melun, 77000
HOP Hôtel-Dieu
Nantes, 44093
HOP Cochin
Paris, 75014
HOP Européen G. Pompidou
Paris, 75908
HOP Robert Debré
Reims, 51092
HOP Civil
Strasbourg, 67091
Germany6 sites
Medizinische Hochschule Hannover
Hanover, 30625
Universitätsklinikum Heidelberg
Heidelberg, 69120
Universitätsklinikum Leipzig
Leipzig, 04109
Universitätsklinikum Mannheim GmbH
Mannheim, 68167
Klinikum der Universität München - Campus Großhadern
München, 81377
Petrus-Krankenhaus
Wuppertal, 42283
Russia4 sites
City Clinical Hospital # 40 of the Moscow Health Department
Moscow, 108814
Moscow 1st State Med.Univ.n.a.I.M.Sechenov
Moscow, 119048
City Clinical Emergency Hospital
Ryazan, 390026
State Budget Institution of Healthcare Leningradskaya region "Kirovskaya Interdistrict Hospital"
Saint Petersburg, 187342
Spain4 sites
Hospital del Mar
Barcelona, 08003
Hospital Vall d'Hebron
Barcelona, 08035
Hospital Puerta del Mar
Cadiz, 11009
CS Parc Taulí
Sabadell, 08208
Belgium3 sites
ULB Hopital Erasme
Brussels, 1070
Centre Hospitalier Universitaire de Liège
Liège, 4000
Ottignies - HOSP St-Pierre
Ottignies, 1340
Netherlands3 sites
Gelre Ziekenhuizen Apeldoorn
Apeldoorn, 7334 DZ
Rijnstate Hospital
Arnhem, 6815 AD
Canisius-Wilhelmina ziekenhuis
Nijmegen, 6532 SZ
Austria2 sites
LKH Klagenfurt am Woerthersee
Klagenfurt, 9020
Wiener Gesundheitsverbund Klinik Favoriten
Vienna, 1100
Italy2 sites
IRCCS San Raffaele
Milan, 20132
Istituto Clinico Humanitas
Rozzano (MI), 20089
Turkey (Türkiye)1 site
Izmir Dr. Suat Seren Gogus Hastaliklari ve Cerrahisi Egitim ve Arastirma Hastanesi
Izmir, 35110
About this study
Official title: 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.
Read more
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
- Being tested
- Standard of care, Alteplase low dose, Alteplase high dose
- Medical subject headings
- Respiratory Distress Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Standard of careProcedure or surgery
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 doseDrug
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.
Alteplase high doseDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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). Receives: 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). Receives: 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). Receives: 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). Receives: Procedure: Standard of care |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
- Asymptomatic; viral RNA detected
- Symptomatic; independent
- Symptomatic; assistance needed
- Hospitalised; no oxygen therapy
- Hospitalised; oxygen by mask or nasal prongs
- Hospitalised; oxygen by NIV or high flow
- Intubation and mechanical ventilation, PaO2/FiO2=150 or SpO2/FiO2=200
- Mechanical ventilation PaO2/FiO2<150 (SpO2/FiO2<200) or vasopressors
- Mechanical ventilation PaO2/FiO2<150 and vasopressors, dialysis, or ECMO
- 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).
Measured: Up to 28 days.
Secondary outcomes (9)
Number of Subjects With Major Bleeding Events (MBE) at Day 6
Number of subjects with major bleeding events (MBE). Major bleeding events (MBE) according to International Society on Thrombosis and Haemostasis [ISTH] definition until Day 6. Definition of a major bleed:
•Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome,
and/or
•Bleeding associated with a reduction in hemoglobin of at least 2 gram/deciliter (1.24 millimole/Liter), or leading to transfusion of two or more units of blood or packed cells
and/or
•Fatal bleed
Measured: From start of treatment (Alteplase) or randomisation (SOC) (day 1) till Day 6, up to 6 days.
All Cause Mortality at Day 28
All cause mortality at Day 28. If it is unknown whether the patient was dead at end of Day 28, then it will be assumed that the patient did not die up to Day 28, regardless of the reason. This unfavorable endpoint is met if:
- the last known status of the patient is 10 on the WHO clinical progression scale by the end of Day 28, or
- vital status is dead within 28 days
Measured: Up to 28 days.
Number of Subjects With Treatment Failure at Day 28
Treatment failure defined as all cause mortality or mechanical ventilation at Day 28.
Measured: Up to 28 days.
Number of Ventilator-free Days at Day 28
Number of ventilator-free days (VFDs) from start of treatment to Day 28. 'Ventilator' is defined as 'assisted breathing' but it refers to mechanical invasive ventilation. The number of VFDs starts from when the patient has a 'lasting' value on the WHO clinical progression scale of ≤ 6, and ends on Day 28. A lasting value of ≤ 6 means that the value cannot exceed 6 at a later timepoint. If the patient is liberated from the ventilator on Day x, then the number of VFDs is 28-x. If a patient has withdrawn consent prior to day 28 then he will have a missing value for VFD. In any case, if the status of the patient at Day 28 is death, as determined from the vital status page then the VFD=0.
Measured: Up to 28 days.
Number of Subjects With Improvement of Sequential (Sepsis-related) Organ Failure Assessment (SOFA) Score by ≥2 Points at Day 6
Number of subjects with improvement of Sequential (sepsis-related) Organ Failure Assessment (SOFA) score by ≥2 points from baseline to end of Day 6. The Sequential Organ Failure Assessment (SOFA) scores six variables: respiratory, coagulation, liver, Cardiovascular, central nervous system and renal. Each variable is score from 0 (best outcome) to 4 (worst outcome) with a total score calculated as the sum of all six variables ranging from 0 (best outcome) to 24 (worst outcome).
Measured: Baseline (Day 0) and Day 6 of treatment
Daily Average PaO2/FiO2 Ratio Change From Baseline to Day 6
Daily average PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change from baseline to Day 6. This assessment was measured approximately 3-times daily. All available values on each of these days, regardless of the position of the patient when being measured, were averaged in order to determine the daily average PaO2/FiO2 ratio for that patient. The higher the value the better the health status of the patient. If the patient was still in hospital during day 6 then the day 6 daily average value was used, if available. If the patient was discharged from hospital prior to day 6 then the daily average at the time of hospital discharge was used as a surrogate for day 6, if available. If the patient died prior to day 6 then there was no imputation but the death handled as failure in the determination of the difference in medians and 95% CI. Based upon this, the change from baseline for each patient was calculated.
Measured: Up to 6 days.
Number of Oxygen-free Days up to Day 28
Number of oxygen-free days (OFD) up to Day 28. Oxygen-free is defined as free from assistance from oxygen support. The number of oxygen-free days starts from when the patient has a 'lasting' value on the WHO clinical progression scale of ≤ 4 and ends on Day 28. A lasting value of ≤ 4 means that the value cannot exceed 4 at a later timepoint. If the patient is liberated from oxygen on Day x, then the number of OFDs is 28-x. If a patient has withdrawn consent prior to day 28 then he will have a missing value for OFD. In any case, if the status of the patient at Day 28 is death, as determined from the vital status page then the OFD=0.
Measured: Up to 28 days.
Length of Hospital Stay up to Day 28
Length of hospital stay up to day 28 was determined based upon the first hospital discharge date, or discharge to another care facility. If the patient died within the first 28 day period, then length of hospital stay was 28.
Measured: Up to 28 days.
Worst PaO2/FiO2 Ratio Change From Baseline to Day 6
Worst PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change from baseline to day 6. This assessment was planned to be measured on each of days 0 to 6. but only whilst the patients was still in hospital. The worst (lowest) daily measurement will be used and the higher the value the better the health status of the patient.
- If the patient was still in hospital during day 6 then the day 6 value was used
- If the patient was discharged from hospital prior to day 6 then the value at the time of hospital discharge was used
- If the patient died prior to day 6 then the last value prior to death was used
- If day 6 value was missing but Day 5 value available, the day 5 value was used
- If day 6 value was missing, no Day 5 value available, but day 7 available, then day 7 value was used
- Otherwise value was set to missing for that patient. Based upon this, the change from baseline for each patient was calculated and used for the analysis.
Measured: Up to 7 days.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Nov 2020
- Study start16 Dec 2020
- Primary completion19 Jul 2022
- Study completion25 Jul 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Acute Respiratory Distress SyndromeStudies of the same condition, open and under way.
- More trials run by Boehringer IngelheimThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- The study comprises two parts: Part 1 (dose-finding, Phase IIb) and Part 2 (confirmatory, Phase III)
- Masking
- None (open label)
- Enrolment
- 104 participants (actual)
Sponsor and investigators
- Lead sponsor
- Boehringer Ingelheim
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04640194
- Sponsor's protocol ID
- 0135-0347
- Other IDs
- 2020-002913-16
- Acronym
- TRISTARDS
- Status last verified
- Mar 2024
- First submitted
- 20 Nov 2020
- Last updated
- 20 Mar 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: After the study is completed and the primary manuscript is accepted for publishing, researchers can use this following link https://www.mystudywindow.com/msw/datasharing to request access to the clinical study documents regarding this study, and upon a signed "Document Sharing Agreement". Also, Researchers can use the following link https://www.mystudywindow.com/msw/datasharing to find information in order to request access to the clinical study data, for this and other listed studies, after the submission of a research proposal and according to the terms outlined in the website. The data shared are the raw clinical study data sets.
Publications
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.
PubMed 39522090
Study at a glance
From the registry record, last updated by the sponsor on 20 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT04640194
- Acronym / sponsor ID
- TRISTARDS / 0135-0347
- Conditions
- Acute Respiratory Distress Syndrome
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 104 participants (actual)
- Lead sponsor
- Boehringer IngelheimIndustry (pharma, biotech, devices)
- Study start
- 16 Dec 2020 (actual)
- Primary completion
- 19 Jul 2022 (actual)
- Study completion
- 25 Jul 2022 (actual)
- First posted
- 23 Nov 2020 (actual)
- Results
- Posted 7 Mar 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 7
- Model description
- The study comprises two parts: Part 1 (dose-finding, Phase IIb) and Part 2 (confirmatory, Phase III)
| Arm | Type | Receives |
|---|---|---|
| Part 1: Alteplase low dose | Experimental | Procedure: Standard of care, Drug: Alteplase low dose0.3 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. |
| Part 1: Alteplase high dose | Experimental | Procedure: Standard of care, Drug: Alteplase high dose0.6 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. |
| Part 1: Standard of Care | Other | Procedure: Standard of careStandard 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. |
| Part 2: Alteplase high dose - non-invasive mechanical ventilation (NIV) patients | Experimental | Procedure: Standard of care, Drug: Alteplase high dose0.6 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). |
| Part 2: Standard of Care - non-invasive mechanical ventilation (NIV) patients | Other | Procedure: Standard of careStandard 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). |
| Part 2: Alteplase high dose - invasive mechanical ventilation (IMV) patients | Experimental | Procedure: Standard of care, Drug: Alteplase high dose0.6 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). |
| Part 2: Standard of Care - invasive mechanical ventilation (IMV) patients | Other | Procedure: Standard of careStandard 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). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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),
- 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
Key exclusion criteria (10 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Standard of careStandard 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. | Procedure or surgery | 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 dose0.3 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. | Drug | Part 1: Alteplase low dose |
| Alteplase high dose0.6 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. | Drug | 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 |
Primary outcome
Time to Clinical Improvement or Hospital Discharge up to Day 28
Time frame: Up to 28 days.
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).
9 secondary outcomes
Number of Subjects With Major Bleeding Events (MBE) at Day 6
Time frame: From start of treatment (Alteplase) or randomisation (SOC) (day 1) till Day 6, up to 6 days.
All Cause Mortality at Day 28
Time frame: Up to 28 days.
Number of Subjects With Treatment Failure at Day 28
Time frame: Up to 28 days.
Number of Ventilator-free Days at Day 28
Time frame: Up to 28 days.
Number of Subjects With Improvement of Sequential (Sepsis-related) Organ Failure Assessment (SOFA) Score by ≥2 Points at Day 6
Time frame: Baseline (Day 0) and Day 6 of treatment
Daily Average PaO2/FiO2 Ratio Change From Baseline to Day 6
Time frame: Up to 6 days.
Number of Oxygen-free Days up to Day 28
Time frame: Up to 28 days.
Length of Hospital Stay up to Day 28
Time frame: Up to 28 days.
Worst PaO2/FiO2 Ratio Change From Baseline to Day 6
Time frame: Up to 7 days.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Mar 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 39522090Landoni 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.
- Related InfoLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. After the study is completed and the primary manuscript is accepted for publishing, researchers can use this following link https://www.mystudywindow.com/msw/datasharing to request access to the clinical study documents regarding this study, and upon a signed "Document Sharing Agreement". Also, Researchers can use the following link https://www.mystudywindow.com/msw/datasharing to find information in order to request access to the clinical study data, for this and other listed studies, after the submission of a research proposal and according to the terms outlined in the website. The data shared are the raw clinical study data sets.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
37 sites in 13 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Alteplase low dose and Alteplase high dose in people with Acute Respiratory Distress Syndrome, run by Boehringer Ingelheim at 37 sites in 13 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 37 sites in France, Germany, Russia, Spain, Belgium and 8 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 7 Mar 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to Clinical Improvement or Hospital Discharge up to Day 28 (time frame: Up to 28 days.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04640194, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Mar 2024.