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

Sponsor

Boehringer Ingelheim (Industry)

Overall Status

Terminated

CT.gov ID

NCT04640194

Collaborator

(none)

104

Enrollment

Locations

Arms

19.3

Actual Duration (Months)

1.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Respiratory Distress Syndrome	Drug: Alteplase Procedure: Standard of care	Phase 2/Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

104 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

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

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Dec 16, 2020

Actual Primary Completion Date :

Jul 13, 2022

Actual Study Completion Date :

Jul 25, 2022

Arms and Interventions

Arm	Intervention/Treatment
Other: Control group Standard of care alone	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.
Experimental: Treatment group A Alteplase (low dose) on top of standard of care	Drug: Alteplase Alteplase 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.
Experimental: Treatment group B Alteplase (high dose) on top of standard of care	Drug: Alteplase Alteplase 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.

Arm

Intervention/Treatment

Other: Control group

Standard of care alone

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.

Experimental: Treatment group A

Alteplase (low dose) on top of standard of care

Drug: Alteplase

Alteplase

Procedure: Standard of care

Experimental: Treatment group B

Alteplase (high dose) on top of standard of care

Drug: Alteplase

Alteplase

Procedure: Standard of care

Outcome Measures

Primary Outcome Measures

Time to clinical improvement or hospital discharge [Up to day 28]
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 [At day 28]
Number of ventilator-free days [From start of treatment to day 28]
Improvement of Sequential (sepsis-related) Organ Failure Assessment (SOFA) score by ≥2 points [From baseline to end of day 6]
The SOFA score ranges from 0 to 6. A higher score indicates a worsening of the symptoms.
Number of major bleeding events (MBE) [Up to day 6]
according to International Society on Thrombosis and Haemostasis (ISTH) definition
Daily average PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change [From baseline to end of day 6]
PaO2: partial oxygen pressure in arterial blood FiO2: fraction of inspired oxygen SpO2: Oxygen saturation
All-cause mortality or on mechanical ventilation [At day 28]
Treatment failure [At Day 28]
part 2: defined as all cause mortality or mechanical ventilation
All cause mortality [At Day 28]
part 2
Number of oxygen-free days [Up to Day 28]
part 2
Length of hospital stay [Up to Day 28]
part 2
Major bleeding events (MBE) [Up to Day 6]
part 2
PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change [From baseline to end of Day 6]
part 2: PaO2: partial oxygen pressure in arterial blood FiO2: fraction of inspired oxygen SpO2: Oxygen saturation

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Instituto Medico Platense	La Plata	Argentina	B1900AVG
2	LKH Klagenfurt am Woerthersee	Klagenfurt	Austria	9020
3	Convent Hospital Barmherzige Brüder	Linz	Austria	4021
4	Wiener Gesundheitsverbund Klinik Favoriten	Vienna	Austria	1100
5	ULB Hopital Erasme	Bruxelles	Belgium	1070
6	Brussels - UNIV UZ Brussel	Jette	Belgium	1090
7	Centre Hospitalier Universitaire de Liège	Liège	Belgium	4000
8	Ottignies - HOSP St-Pierre	Ottignies	Belgium	1340
9	Hospital Luxemburgo	Belo Horizonte	Brazil	32380-490
10	Faculdade de Medicina de Botucatu - UNESP	Botucatu	Brazil	18607-780
11	Hospital Samaritano de Campinas HSC	Campinas	Brazil	13041-304
12	Hospital Sao Jose	Criciuma	Brazil	88801250
13	Hospital Nossa Senhora das Gracas	Curitiba	Brazil	80810-040
14	Irmandade da Santa Casa de Misericórdia de Porto Alegre	Porto Alegre	Brazil	90020-090
15	Hospital Mae de Deus	Porto Alegre	Brazil	90470-340
16	H.C.da Fac. de Medicina de Ribeirao Preto	Ribeirao Preto	Brazil	14048-900
17	Hvidovre Hospital	Hvidovre	Denmark	2650
18	HOP Bicêtre	Le Kremlin Bicêtre cedex	France	94275
19	HOP Roger Salengro	Lille	France	59037
20	HOP Melun-Sénart	Melun	France	77000
21	HOP Hôtel-Dieu	Nantes	France	44093
22	HOP l'Archet	Nice	France	06202
23	HOP La Source	Orléans	France	45067
24	HOP Européen G. Pompidou	Paris cedex 15	France	75908
25	HOP Saint-Antoine	Paris	France	75012
26	HOP Cochin	Paris	France	75014
27	HOP Pierre Bénite	Pierre Bénite	France	69310
28	HOP Robert Debré	Reims	France	51092
29	HOP Civil	Strasbourg cedex	France	67091
30	HOP Brabois	Vandoeuvre-lès-Nancy	France	54500
31	Medizinische Hochschule Hannover	Hannover	Germany	30625
32	Universitätsklinikum Heidelberg	Heidelberg	Germany	69120
33	Universitätsklinikum Leipzig	Leipzig	Germany	04109
34	Universitätsklinikum Mannheim GmbH	Mannheim	Germany	68167
35	Klinikum der Universität München - Campus Großhadern	München	Germany	81377
36	Petrus-Krankenhaus	Wuppertal	Germany	42283
37	Bangalore Medical College and Research Institute	Bengaluru	India	560002
38	Nirmal Hospital Pvt. Ltd.	Gujarat	India	395002
39	Aster Prime Hospitals	Hyderbad	India	500038
40	Maharaja Agrasen Superspeciality Hospital	Jaipur	India	302039
41	GSVM Medical College	Kanpur	India	208002
42	JSS Medical College and Hospital	Mysore	India	570015
43	Suyog Hospital	Nashik	India	422003
44	Magnum Heart Institute	Nashik	India	422005
45	Vishwaraj Superspeciality Hospital	Pune	India	412201
46	Dayanand Medical College & Hospital	Punjab	India	141001
47	Rhythm Heart Institute	Vadodara	India	390022
48	King George Hospital	Visakhapatnam	India	530002
49	IRCCS San Raffaele	Milano	Italy	20132
50	Istituto Clinico Humanitas	Rozzano (MI)	Italy	20089
51	Ospedali Riuniti di Ancona	Torrette Di Ancona (AN)	Italy	60123
52	Hospital Queen Elizabeth	Kota Kinabalu, Sabah	Malaysia	88586
53	University of Malaya Medical Centre	Kuala Lumpur	Malaysia	59100
54	Hospital Miri	Miri	Malaysia	98000
55	Hospital Cardiologica Aguascalientes	Aguascalientes	Mexico	20230
56	Hospital General de Occidente de la Secretaría de Salud Jalisco	Guadalajara	Mexico	45170
57	Servicios Hospitalarios de México S.A. de C.V.	Mexico	Mexico	31064
58	Gelre Ziekenhuizen Apeldoorn	Apeldoorn	Netherlands	7334 DZ
59	Rijnstate Hospital	Arnhem	Netherlands	6815 AD
60	Canisius-Wilhelmina ziekenhuis	Nijmegen	Netherlands	6532 SZ
61	St. Luke's Hospital in Boleslawiec Center for Prevention and Treatment of Strokes	Boleslawiec	Poland	59700
62	Centro Hospitalar Universitário do Porto, EPE - Hospital de Santo António	Porto	Portugal	4099-001
63	Matei Bals Institute of Infectious Disease, Bucharest	Bucharest	Romania	021105
64	Clin. Hos. of Infectious and Tropical Diseases "Victor Babes"	Bucharest	Romania	030303
65	City Clinical Hospital # 40 of the Moscow Health Department	Moscow	Russian Federation	108814
66	Moscow 1st State Med.Univ.n.a.I.M.Sechenov	Moscow	Russian Federation	119048
67	State Budgetary Institution of Healthcare "Clinical Hospital No. 4"	Penza	Russian Federation	440067
68	City Clinical Emergency Hospital	Ryazan	Russian Federation	390026
69	State Budget Institution of Healthcare Leningradskaya region "Kirovskaya Interdistrict Hospital"	Saint Petersburg	Russian Federation	187342
70	City Clinical Hospital No. 15, St. Petersburg	St. Petersburg	Russian Federation	198205
71	Pokrovskaya City Hospital, St.Petersburg	St. Petersburg	Russian Federation	199106
72	Dr JM Engelbrecht	Somerset West, Western Cape	South Africa	7130
73	Hospital del Mar	Barcelona	Spain	08003
74	Hospital Vall d'Hebron	Barcelona	Spain	08035
75	Hospital Puerta del Mar	Cádiz	Spain	11009
76	CS Parc Taulí	Sabadell	Spain	08208
77	Hospital Mútua Terrassa	Terrassa	Spain	08221
78	Hospital Politècnic La Fe	Valencia	Spain	46026
79	Acibadem Universitesi Atakent Hastanesi	Istanbul	Turkey	34303
80	Sureyyapasa Gogus Hast. ve Gogus Cer. Egit. ve Aras. Has.	Istanbul	Turkey	34844
81	Istanbul Lutfi Kirdar Sehir Hastanesi	Istanbul	Turkey	34865
82	Izmir Dr. Suat Seren Gogus Hastaliklari ve Cerrahisi Egitim ve Arastirma Hastanesi	Izmir	Turkey	35110
83	Kocaeli Universitesi Tip Fakultesi	Kocaeli	Turkey	41380
84	Karadeniz Teknik Universitesi Tip Fakultesi	Trabzon	Turkey	61080