Clinical trial NCT04640194: A Study to Test Whether Different Doses of Alteplase Help People With Severe Breathing Problems Because of COVID-19
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
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Acute Respiratory Distress Syndrome
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2020-11-23
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study comprises two parts: Part 1 (dose-finding, Phase IIb) and Part 2 (confirmatory, Phase III)
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Time to Clinical Improvement or Hospital Discharge up to Day 28
timeFrame: Up to 28 days.
Secondary outcomes:
measure: Number of Subjects With Major Bleeding Events (MBE) at Day 6
timeFrame: From start of treatment (Alteplase) or randomisation (SOC) (day 1) till Day 6, up to 6 days.
measure: All Cause Mortality at Day 28
timeFrame: Up to 28 days.
measure: Number of Subjects With Treatment Failure at Day 28
timeFrame: Up to 28 days.
measure: Number of Ventilator-free Days at Day 28
timeFrame: Up to 28 days.
measure: Number of Subjects With Improvement of Sequential (Sepsis-related) Organ Failure Assessment (SOFA) Score by ≥2 Points at Day 6
timeFrame: Baseline (Day 0) and Day 6 of treatment
measure: Daily Average PaO2/FiO2 Ratio Change From Baseline to Day 6
timeFrame: Up to 6 days.
measure: Number of Oxygen-free Days up to Day 28
timeFrame: Up to 28 days.
measure: Length of Hospital Stay up to Day 28
timeFrame: Up to 28 days.
measure: Worst PaO2/FiO2 Ratio Change From Baseline to Day 6
timeFrame: Up to 7 days.
Other outcomes:
Locations:
city: Klagenfurt
country: Austria
facility: LKH Klagenfurt am Woerthersee
city: Vienna
country: Austria
facility: Wiener Gesundheitsverbund Klinik Favoriten
city: Bruxelles
country: Belgium
facility: ULB Hopital Erasme
city: Liège
country: Belgium
facility: Centre Hospitalier Universitaire de Liège
city: Ottignies
country: Belgium
facility: Ottignies - HOSP St-Pierre
city: Porto Alegre
country: Brazil
facility: Hospital Mae de Deus
city: Le Kremlin Bicêtre cedex
country: France
facility: HOP Bicêtre
city: Lille
country: France
facility: HOP Roger Salengro
city: Melun
country: France
facility: HOP Melun-Sénart
city: Nantes
country: France
facility: HOP Hôtel-Dieu
city: Paris cedex 15
country: France
facility: HOP Européen G. Pompidou
city: Paris
country: France
facility: HOP Cochin
city: Reims
country: France
facility: HOP Robert Debré
city: Strasbourg cedex
country: France
facility: HOP Civil
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Mannheim
country: Germany
facility: Universitätsklinikum Mannheim GmbH
city: München
country: Germany
facility: Klinikum der Universität München - Campus Großhadern
city: Wuppertal
country: Germany
facility: Petrus-Krankenhaus
city: Visakhapatnam
country: India
facility: King George Hospital
city: Milano
country: Italy
facility: IRCCS San Raffaele
city: Rozzano (MI)
country: Italy
facility: Istituto Clinico Humanitas
city: Miri
country: Malaysia
facility: Hospital Miri
city: Aguascalientes
country: Mexico
facility: Hospital Cardiologica Aguascalientes
city: Apeldoorn
country: Netherlands
facility: Gelre Ziekenhuizen Apeldoorn
city: Arnhem
country: Netherlands
facility: Rijnstate Hospital
city: Nijmegen
country: Netherlands
facility: Canisius-Wilhelmina ziekenhuis
city: Moscow
country: Russian Federation
facility: City Clinical Hospital # 40 of the Moscow Health Department
city: Moscow
country: Russian Federation
facility: Moscow 1st State Med.Univ.n.a.I.M.Sechenov
city: Ryazan
country: Russian Federation
facility: City Clinical Emergency Hospital
city: Saint Petersburg
country: Russian Federation
facility: State Budget Institution of Healthcare Leningradskaya region "Kirovskaya Interdistrict Hospital"
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Cádiz
country: Spain
facility: Hospital Puerta del Mar
city: Sabadell
country: Spain
facility: CS Parc Taulí
city: Izmir
country: Turkey
facility: Izmir Dr. Suat Seren Gogus Hastaliklari ve Cerrahisi Egitim ve Arastirma Hastanesi
Study officials:
References: