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

Primary Purpose

Acute Respiratory Distress Syndrome

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Alteplase
Standard of care
Sponsored by
Boehringer Ingelheim
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Respiratory Distress Syndrome

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

  • LKH Klagenfurt am Woerthersee
  • Wiener Gesundheitsverbund Klinik Favoriten
  • ULB Hopital Erasme
  • Centre Hospitalier Universitaire de Liège
  • Ottignies - HOSP St-Pierre
  • Hospital Mae de Deus
  • HOP Bicêtre
  • HOP Roger Salengro
  • HOP Melun-Sénart
  • HOP Hôtel-Dieu
  • HOP Européen G. Pompidou
  • HOP Cochin
  • HOP Robert Debré
  • HOP Civil
  • Medizinische Hochschule Hannover
  • Universitätsklinikum Heidelberg
  • Universitätsklinikum Leipzig
  • Universitätsklinikum Mannheim GmbH
  • Klinikum der Universität München - Campus Großhadern
  • Petrus-Krankenhaus
  • King George Hospital
  • IRCCS San Raffaele
  • Istituto Clinico Humanitas
  • Hospital Miri
  • Hospital Cardiologica Aguascalientes
  • Gelre Ziekenhuizen Apeldoorn
  • Rijnstate Hospital
  • Canisius-Wilhelmina ziekenhuis
  • City Clinical Hospital # 40 of the Moscow Health Department
  • Moscow 1st State Med.Univ.n.a.I.M.Sechenov
  • City Clinical Emergency Hospital
  • State Budget Institution of Healthcare Leningradskaya region "Kirovskaya Interdistrict Hospital"
  • Hospital del Mar
  • Hospital Vall d'Hebron
  • Hospital Puerta del Mar
  • CS Parc Taulí
  • Izmir Dr. Suat Seren Gogus Hastaliklari ve Cerrahisi Egitim ve Arastirma Hastanesi

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Other

Experimental

Experimental

Arm Label

Control group

Treatment group A

Treatment group B

Arm Description

Standard of care alone

Alteplase (low dose) on top of standard of care

Alteplase (high dose) on top of standard of care

Outcomes

Primary Outcome Measures

Time to clinical improvement or hospital discharge
Time from randomisation to either an improvement of two points on the 11-point WHO Clinical Progression Scale or discharge from the hospital, whichever comes first. The WHO Clinical Progression Scale ranges from 0 to 10. A higher score indicates a worsening of the patient status.

Secondary Outcome Measures

All cause mortality
Number of ventilator-free days
Improvement of Sequential (sepsis-related) Organ Failure Assessment (SOFA) score by ≥2 points
The SOFA score ranges from 0 to 6. A higher score indicates a worsening of the symptoms.
Number of major bleeding events (MBE)
according to International Society on Thrombosis and Haemostasis (ISTH) definition
Daily average PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change
PaO2: partial oxygen pressure in arterial blood FiO2: fraction of inspired oxygen SpO2: Oxygen saturation
All-cause mortality or on mechanical ventilation
Treatment failure
part 2: defined as all cause mortality or mechanical ventilation
All cause mortality
part 2
Number of oxygen-free days
part 2
Length of hospital stay
part 2
Major bleeding events (MBE)
part 2
PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change
part 2: PaO2: partial oxygen pressure in arterial blood FiO2: fraction of inspired oxygen SpO2: Oxygen saturation

Full Information

First Posted
November 20, 2020
Last Updated
December 12, 2022
Sponsor
Boehringer Ingelheim
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1. Study Identification

Unique Protocol Identification Number
NCT04640194
Brief Title
A Study to Test Whether Different Doses of Alteplase Help People With Severe Breathing Problems Because of COVID-19
Acronym
TRISTARDS
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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Terminated
Why Stopped
Sponsor decision
Study Start Date
December 16, 2020 (Actual)
Primary Completion Date
July 19, 2022 (Actual)
Study Completion Date
July 25, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Boehringer Ingelheim

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Respiratory Distress Syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Model Description
The study comprises two parts: Part 1 (dose-finding, Phase IIb) and Part 2 (confirmatory, Phase III)
Masking
None (Open Label)
Allocation
Randomized
Enrollment
104 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Control group
Arm Type
Other
Arm Description
Standard of care alone
Arm Title
Treatment group A
Arm Type
Experimental
Arm Description
Alteplase (low dose) on top of standard of care
Arm Title
Treatment group B
Arm Type
Experimental
Arm Description
Alteplase (high dose) on top of standard of care
Intervention Type
Drug
Intervention Name(s)
Alteplase
Intervention Description
Alteplase
Intervention Type
Procedure
Intervention Name(s)
Standard of care
Intervention Description
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.
Primary Outcome Measure Information:
Title
Time to clinical improvement or hospital discharge
Description
Time from randomisation to either an improvement of two points on the 11-point WHO Clinical Progression Scale or discharge from the hospital, whichever comes first. The WHO Clinical Progression Scale ranges from 0 to 10. A higher score indicates a worsening of the patient status.
Time Frame
Up to day 28
Secondary Outcome Measure Information:
Title
All cause mortality
Time Frame
At day 28
Title
Number of ventilator-free days
Time Frame
From start of treatment to day 28
Title
Improvement of Sequential (sepsis-related) Organ Failure Assessment (SOFA) score by ≥2 points
Description
The SOFA score ranges from 0 to 6. A higher score indicates a worsening of the symptoms.
Time Frame
From baseline to end of day 6
Title
Number of major bleeding events (MBE)
Description
according to International Society on Thrombosis and Haemostasis (ISTH) definition
Time Frame
Up to day 6
Title
Daily average PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change
Description
PaO2: partial oxygen pressure in arterial blood FiO2: fraction of inspired oxygen SpO2: Oxygen saturation
Time Frame
From baseline to end of day 6
Title
All-cause mortality or on mechanical ventilation
Time Frame
At day 28
Title
Treatment failure
Description
part 2: defined as all cause mortality or mechanical ventilation
Time Frame
At Day 28
Title
All cause mortality
Description
part 2
Time Frame
At Day 28
Title
Number of oxygen-free days
Description
part 2
Time Frame
Up to Day 28
Title
Length of hospital stay
Description
part 2
Time Frame
Up to Day 28
Title
Major bleeding events (MBE)
Description
part 2
Time Frame
Up to Day 6
Title
PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change
Description
part 2: PaO2: partial oxygen pressure in arterial blood FiO2: fraction of inspired oxygen SpO2: Oxygen saturation
Time Frame
From baseline to end of Day 6

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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 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.
Facility Information:
Facility Name
LKH Klagenfurt am Woerthersee
City
Klagenfurt
ZIP/Postal Code
9020
Country
Austria
Facility Name
Wiener Gesundheitsverbund Klinik Favoriten
City
Vienna
ZIP/Postal Code
1100
Country
Austria
Facility Name
ULB Hopital Erasme
City
Bruxelles
ZIP/Postal Code
1070
Country
Belgium
Facility Name
Centre Hospitalier Universitaire de Liège
City
Liège
ZIP/Postal Code
4000
Country
Belgium
Facility Name
Ottignies - HOSP St-Pierre
City
Ottignies
ZIP/Postal Code
1340
Country
Belgium
Facility Name
Hospital Mae de Deus
City
Porto Alegre
ZIP/Postal Code
90470-340
Country
Brazil
Facility Name
HOP Bicêtre
City
Le Kremlin Bicêtre cedex
ZIP/Postal Code
94275
Country
France
Facility Name
HOP Roger Salengro
City
Lille
ZIP/Postal Code
59037
Country
France
Facility Name
HOP Melun-Sénart
City
Melun
ZIP/Postal Code
77000
Country
France
Facility Name
HOP Hôtel-Dieu
City
Nantes
ZIP/Postal Code
44093
Country
France
Facility Name
HOP Européen G. Pompidou
City
Paris cedex 15
ZIP/Postal Code
75908
Country
France
Facility Name
HOP Cochin
City
Paris
ZIP/Postal Code
75014
Country
France
Facility Name
HOP Robert Debré
City
Reims
ZIP/Postal Code
51092
Country
France
Facility Name
HOP Civil
City
Strasbourg cedex
ZIP/Postal Code
67091
Country
France
Facility Name
Medizinische Hochschule Hannover
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Facility Name
Universitätsklinikum Heidelberg
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
Facility Name
Universitätsklinikum Leipzig
City
Leipzig
ZIP/Postal Code
04109
Country
Germany
Facility Name
Universitätsklinikum Mannheim GmbH
City
Mannheim
ZIP/Postal Code
68167
Country
Germany
Facility Name
Klinikum der Universität München - Campus Großhadern
City
München
ZIP/Postal Code
81377
Country
Germany
Facility Name
Petrus-Krankenhaus
City
Wuppertal
ZIP/Postal Code
42283
Country
Germany
Facility Name
King George Hospital
City
Visakhapatnam
ZIP/Postal Code
530002
Country
India
Facility Name
IRCCS San Raffaele
City
Milano
ZIP/Postal Code
20132
Country
Italy
Facility Name
Istituto Clinico Humanitas
City
Rozzano (MI)
ZIP/Postal Code
20089
Country
Italy
Facility Name
Hospital Miri
City
Miri
ZIP/Postal Code
98000
Country
Malaysia
Facility Name
Hospital Cardiologica Aguascalientes
City
Aguascalientes
ZIP/Postal Code
20230
Country
Mexico
Facility Name
Gelre Ziekenhuizen Apeldoorn
City
Apeldoorn
ZIP/Postal Code
7334 DZ
Country
Netherlands
Facility Name
Rijnstate Hospital
City
Arnhem
ZIP/Postal Code
6815 AD
Country
Netherlands
Facility Name
Canisius-Wilhelmina ziekenhuis
City
Nijmegen
ZIP/Postal Code
6532 SZ
Country
Netherlands
Facility Name
City Clinical Hospital # 40 of the Moscow Health Department
City
Moscow
ZIP/Postal Code
108814
Country
Russian Federation
Facility Name
Moscow 1st State Med.Univ.n.a.I.M.Sechenov
City
Moscow
ZIP/Postal Code
119048
Country
Russian Federation
Facility Name
City Clinical Emergency Hospital
City
Ryazan
ZIP/Postal Code
390026
Country
Russian Federation
Facility Name
State Budget Institution of Healthcare Leningradskaya region "Kirovskaya Interdistrict Hospital"
City
Saint Petersburg
ZIP/Postal Code
187342
Country
Russian Federation
Facility Name
Hospital del Mar
City
Barcelona
ZIP/Postal Code
08003
Country
Spain
Facility Name
Hospital Vall d'Hebron
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Hospital Puerta del Mar
City
Cádiz
ZIP/Postal Code
11009
Country
Spain
Facility Name
CS Parc Taulí
City
Sabadell
ZIP/Postal Code
08208
Country
Spain
Facility Name
Izmir Dr. Suat Seren Gogus Hastaliklari ve Cerrahisi Egitim ve Arastirma Hastanesi
City
Izmir
ZIP/Postal Code
35110
Country
Turkey

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
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.
IPD Sharing 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.
IPD Sharing 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'.
IPD Sharing URL
https://www.mystudywindow.com/msw/datasharing
Links:
URL
https://www.mystudywindow.com/
Description
Related Info

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

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