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

Acute Respiratory Distress Syndrome Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04640194
• Other study ID #: 0135-0347
• Secondary ID: 2020-002913-16
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: December 16, 2020
• Est. completion date: July 25, 2022

Study information

• Verified date: March 2024
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 104
• Est. completion date: July 25, 2022
• Est. primary completion date: July 19, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Respiratory Distress Syndrome
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Newborn
• Syndrome

Intervention

Procedure:
• 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.

Drug:
• 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.
• 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.

Locations

Country	Name	City	State
Austria	LKH Klagenfurt am Woerthersee	Klagenfurt
Austria	Wiener Gesundheitsverbund Klinik Favoriten	Vienna
Belgium	ULB Hopital Erasme	Bruxelles
Belgium	Centre Hospitalier Universitaire de Liège	Liège
Belgium	Ottignies - HOSP St-Pierre	Ottignies
Brazil	Hospital Mae de Deus	Porto Alegre
France	HOP Bicêtre	Le Kremlin Bicêtre cedex
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 cedex 15
France	HOP Robert Debré	Reims
France	HOP Civil	Strasbourg cedex
Germany	Medizinische Hochschule Hannover	Hannover
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
India	King George Hospital	Visakhapatnam
Italy	IRCCS San Raffaele	Milano
Italy	Istituto Clinico Humanitas	Rozzano (MI)
Malaysia	Hospital Miri	Miri
Mexico	Hospital Cardiologica Aguascalientes	Aguascalientes
Netherlands	Gelre Ziekenhuizen Apeldoorn	Apeldoorn
Netherlands	Rijnstate Hospital	Arnhem
Netherlands	Canisius-Wilhelmina ziekenhuis	Nijmegen
Russian Federation	City Clinical Hospital # 40 of the Moscow Health Department	Moscow
Russian Federation	Moscow 1st State Med.Univ.n.a.I.M.Sechenov	Moscow
Russian Federation	City Clinical Emergency Hospital	Ryazan
Russian Federation	State Budget Institution of Healthcare Leningradskaya region "Kirovskaya Interdistrict Hospital"	Saint Petersburg
Spain	Hospital del Mar	Barcelona
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital Puerta del Mar	Cádiz
Spain	CS Parc Taulí	Sabadell
Turkey	Izmir Dr. Suat Seren Gogus Hastaliklari ve Cerrahisi Egitim ve Arastirma Hastanesi	Izmir

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

Austria,  Belgium,  Brazil,  France,  Germany,  India,  Italy,  Malaysia,  Mexico,  Netherlands,  Russian Federation,  Spain,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).	Up to 28 days.
Secondary	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	From start of treatment (Alteplase) or randomisation (SOC) (day 1) till Day 6, up to 6 days.
Secondary	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	Up to 28 days.
Secondary	Number of Subjects With Treatment Failure at Day 28	Treatment failure defined as all cause mortality or mechanical ventilation at Day 28.	Up to 28 days.
Secondary	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.	Up to 28 days.
Secondary	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).	Baseline (Day 0) and Day 6 of treatment
Secondary	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.	Up to 6 days.
Secondary	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.	Up to 28 days.
Secondary	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.	Up to 28 days.
Secondary	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.	Up to 7 days.

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