Clinical Trials Register

Summary
EudraCT Number:	2020-002913-16
Sponsor's Protocol Code Number:	0135-0347
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-12-29
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2020-002913-16

A.3

Full title of the trial

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.

Studio TRISTARDS - ThRombolysIS Therapy for ARDS (terapia trombolitica per distress respiratorio acuto)
Studio adattivo di fase IIb/III, operativamente senza soluzione di continuità, in aperto, randomizzato, sequenziale, a gruppi paralleli per valutare l'efficacia e la sicurezza del trattamento con alteplase endovenoso somministrato una volta al giorno per al massimo 5 giorni in aggiunta al trattamento standard di cura (SOC) rispetto al solo SOC, in pazienti con sindrome da distress respiratorio acuto (ARDS) provocata da COVID-19.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

The TRISTARDS trial - ThRombolysIS Therapy for ARDS A study to test
whether different doses of alteplase help people with severe breathing
problems because of COVID 19.

Studio TRISTARDS - ThRombolysIS Therapy for ARDS (terapia trombolitica per distress respiratorio acuto) - Uno studio per testare se dosi diverse di alteplase aiutino persone con problemi respiratori gravi
dovuti a COVID 19.

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

0135-0347

A.5.4

Other Identifiers

Name:

Number:

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	BOEHRINGER-INGELHEIM ITALIA S.P.A.
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Boehringer Ingelheim Italia S.p.A.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Boehringer Ingelheim Pharma GmbH & Co. KG
B.5.2	Functional name of contact point	CT Disclosure & Data Transparency
B.5.3	Address:
B.5.3.1	Street Address	Binger Strasse 173
B.5.3.2	Town/ city	Ingelheim am Rhein
B.5.3.3	Post code	55216
B.5.3.4	Country	Germany
B.5.4	Telephone number	+498002430127
B.5.5	Fax number	+498008217119
B.5.6	E-mail	clintriage.rdg@boehringer-ingelheim.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Alteplase Powder and Solvent for Solution for Injection/Infusion (TPA-05, 50 mg/vial)
D.3.2	Product code	[-]
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ALTEPLASI
D.3.9.1	CAS number	105857-23-6
D.3.9.2	Current sponsor code	-
D.3.9.4	EV Substance Code	SUB05378MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	biotechnologically manufactured and isolated from hamster ovarian cells

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute respiratory distress syndrome caused by Covid-19

Sindrome da distress respiratorio acuto (ARDS) provocata da COVID-19

E.1.1.1

Medical condition in easily understood language

Severe breathing problems caused by Covid-19

Gravi problemi respiratori dovuti a COVID-19

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10001052
E.1.2	Term	Acute respiratory distress syndrome
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy and safety of intravenous alteplase in ARDS triggered by COVID-19.

L’obiettivo primario è valutare l’efficacia e la sicurezza di alteplase in endovena nella sindrome da distress respiratorio provocata da COVID-19.

E.2.2

Secondary objectives of the trial

Not applicable

Non applicabile

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Age >= 18 years (or above legal age, e.g. UK >=16 years)
2.ARDS with PaO2 (see note 1)/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)
Note 1: or estimation of PaO2/FiO2 from pulse oximetry (SpO2/FiO2)
3.SARS-CoV-2 positive (laboratory-confirmed RT-PCR test)
4.Fibrinogen level >= upper limit of normal
5.D-Dimer >= 3-fold of upper limit of normal (ULN) according to local
laboratory
6.Signed and dated written informed consent in accordance with ICH
Good Clinical Practice (GCP) and local legislation prior to admission to
the trial.

I criteri di eligibilità sono gli stessi per la parte 1 e per la parte 2.
I pazienti che partecipano alla parte 1 non sono eligibili per la parte 2.
1.Eta' >= 18 anni
2.ARDS con rapporto PaO2 (vedi nota 1)/FiO2 >100 e <=300, sia con supporto di ventilazione non invasiva che con ventilazione meccanica (<48 ore dall’intubazione) con:
•opacita' bilaterale ai raggi X del torace e TAC (non completamente attribuibile a effusioni, collasso lobulare/polmonare o noduli)
•insufficienza respiratoria (non completamente attribuibile a scompenso cardiac/accumulo di liquidi)
Nota 1: o stima di PaO2/FiO2 dall’ossimetria (SpO2/FiO2) (si veda l’Appendice 10.3 del protocollo per la stima di SpO2/FiO2).
3.Positivita' a SARS-CoV-2 (confermata dal test di laboratorio RT PCR)
4.Livello di fibrinogeno >= il limite superiore di normalita' (in accordo ai valori del laboratorio locale)
5.D-Dimero >= 3volte il limite superiore di normalità (ULN) in accordo ai valori del laboratorio locale
6.Firma e data del consenso informato in accoro alle ICH Good Clinical Practice (GCP) e alla normativa locale prima del coinvolgimento nello studio.

E.4

Principal exclusion criteria

1. Massive confirmed pulmonary embolism (PE) with haemodynamic instability at trial entry
2. Patients on mechanical ventilation for longer than 48 hours
3. 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
4. Has a Do-Not-Intubate (DNI) or Do-Not-Resuscitate (DNR) order
5. In the opinion of the investigator, is not expected to survive for > 48 hours after admission
6. Patients with known hypersensitivity to the active substance
alteplase, gentamicin (a trace residue from the manufacturing process)
or to any of the excipients
7. Significant bleeding disorder at present or within the past 3 months,
known haemorrhagic diathesis
8. Patients receiving effective oral anticoagulant treatment, e.g.
vitamin K antagonists with INR >1.3, or any direct oral anticoagulant
within the past 48 hours
9. Any history of central nervous system damage (i.e. neoplasm,
aneurysm, intracranial or spinal surgery)
10. History or evidence or suspicion of intracranial haemorrhage
including sub-arachnoid haemorrhage
11. Severe uncontrolled arterial hypertension (according to the
investigator`s judgement)
12. Major surgery or significant trauma in the past 10 days, recent
trauma to head or cranium
13. Cardiac arrest and/or cardiopulmonary resuscitation during the
current hospital stay
14. Obstetrical delivery within the past 10 days
15. Severe hepatic dysfunction, including biopsy confirmed hepatic
cirrhosis, portal hypertension, hepatic encephalopathy, or active
hepatitis
16. Bacterial endocarditis, pericarditis
17. Acute pancreatitis
18. Documented ulcerative gastro-intestinal disease during the last 3
months
19. Severe heart failure (New York Heart Association Class IV)
20. Arterial aneurysms, arterial/venous malformations
21. Malignancy (Stage IV)
22. Haemorrhagic stroke or stroke of unknown origin at any time
23. Ischaemic stroke or transient ischaemic attack (TIA) in the
preceding 6 months
Further criteria apply.

1.Massiva embolia polmonare con instabilità emodinamica confermata al momento dell’inclusione nello studio
2.Pazienti con ventilazione meccanica per più di 48 ore
3.Malattia polmonare cronica, cioè con FEV1 nota <50%, con ossigeno terapia o steroidi orali o ospedalizzazione per esacerbazione entro i 12 mesi precedenti o malattie polmonari croniche significative a giudizio dello sperimentatore o ipertensione arteriosa polmonare primaria
4.Richiesta del paziente di non intubare o non rianimare
5.A giudizio dello sperimentatore aspettativa di sopravvivenza non superiore alle 48 ore dall’ospedalizzazione
6.Pazienti con ipersensibilità nota alla sostanza attiva alteplase, alla gentamicina o a qualsiasi eccipiente.
7.Disordini significativi di sanguinamenti attuali o entro i 3 mesi precedenti, diatesi emorragica nota.
8.Pazienti in trattamento con anticoagulanti orali come antagonisti della vitamina K con un INR >1.3, o qualsiasi anticoagulante orale diretto assunto nelle precedenti 48 ore.
9.Storia di danno al sistema nervosa centrale
10.Storia o evidenza o sospetto di emorragia intracranica incluso l’emorragia sub aracnoidea.
11.Severa ipertensione arteriosa non controllata
12.Chirurgia maggiore o trauma significativo negli ultimi 10 giorni, trauma recente alla testa o al cranio.
13.Arresto cardiaco o rianimazione cardiopolmonare durante l’attuale ospedalizzazione
14.Parto negli ultimi 10 giorni
15.Severa disfunzione epatica, incluso la cirrosi epatica confermata da biopsia, ipertensione portale, encefalopatia epatica, o epatiti attive.
16.Endocardite batterica, pericardite
17.Pancreatite acuta
18.Malattia ulcerative gastro intestinale documentata durante gli ultimi 3 mesi
19.Insufficienza cardiaca severa
20.Aneurisma dell’arteria, malformazioni arteriose/venose
21.Cancro (Stadio IV)
22.Ictus emorragico o ictus di origine sconosciuta in qualsiasi momento
23.Ictus ischemico o attacco ischemico transitorio (TIA) negli ultimi 6 mesi
24.Pazienti che devono o desiderano continuare ad assumere farmaci non permessi o qualsiasi farmaco considerato in grado di interferire con la sicurezza dello studio. Il re-screening è permesso una sola volta durante la stessa ospedalizzazione.
25.Donne in gravidanza
26.Malattia renale allo stadio terminale (stadio = 4) o necessità di trapianto renale al baseline.
27.Necessità di ossigenazione extracorporea (ECMO) al baseline
28.Conta piastrinica <100 x 109/L o storia di trombocitopenia indotta da eparina
29.Puntura lombare entro i 3 giorni precedenti
30.Aneurisma addominale o toracico noto
31.Tubercolosi attiva.

E.5 End points

E.5.1

Primary end point(s)

1) Time to clinical improvement or hospital discharge up to Day 28,
defined as the time from randomization to either an improvement of two
points on the 11-point WHO Clinical Progression Scale or discharge from
the hospital, whichever comes first.

1) L’endpoint principale è dato dal primo evento che si verifica tra il tempo intercorso per il miglioramento clinico o la dimissione dall’ospedale fino al giorno 28, definito come il tempo dalla randomizzazione al miglioramento di due punti della scala WHO a 11 punti sulla progressione clinica o alla dimissione dall’ospedale.

E.5.1.1

Timepoint(s) of evaluation of this end point

1) up to day 28

1) fino al giorno 28

E.5.2

Secondary end point(s)

1) All cause mortality at Day 28
2) Number of ventilator-free days from start of treatment to Day 28
3) Improvement of Sequential (sepsis-related) Organ Failure Assessment (SOFA) score by >=2 points from baseline to end of Day 6
4) Major bleeding events (MBE) (according to International Society on Thrombosis and Haemostasis [ISTH] definition until Day 6
5) Daily average PaO2/FiO2 ratio (or inferred PaO2/FiO2 ratio from SpO2) change from baseline to Day 6
6) All-cause mortality or on mechanical ventilation at Day 28

1)Tutte le cause di morte al giorno 28
2)Il numero di giorni liberi da ventilazione dall’inizio del trattamento al giorno 28
3)Miglioramento di almeno 2 punti del punteggio Sequential (sepsis-related) Organ Failure Assessment (SOFA) dal basale alla fine del giorno 6
4)Eventi di sanguinamento maggiore (in accord alle definizioni della International Society on Thrombosis and Haemostasis [ISTH]) fino al giorno 6
5)Variazioni della media giornaliera del rapporto PaO2/FiO2 (o rapporto PaO2/FiO2 inferito da SpO2) dal basale al giorno 6
6)Tutte le cause di mortalità o ventilazione meccanica al giorno 28.

E.5.2.1

Timepoint(s) of evaluation of this end point

1) Day 28
2) Day 28
3) Day 6
4) Day 6
5) Day 6
6) Day 28

1) Giorno 28
2) Giorno 28
3) Giorno 6
4) Giorno 6
5) Giorno 6
6) Giorno 28

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

terapia standard

standard of care

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

China

Russian Federation

Austria

Belgium

Denmark

France

Germany

Italy

Netherlands

Portugal

Spain

Sweden

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

178

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2020-12-29.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

Yes

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

200

F.4.2.2

In the whole clinical trial

270

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

none

nessuna

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-12-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-12-24

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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