Clinical Trials Register

Summary
EudraCT Number:	2015-001830-12
Sponsor's Protocol Code Number:	CTHC007
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-02-16
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

2015-001830-12

A.3

Full title of the trial

Safety and Efficacy of Low Molecular Weight Heparin for 72 Hours Followed by Dabigatran for the Treatment of Acute Intermediate-Risk Pulmonary Embolism (Pulmonary Embolism International Trial - PEITHO-2)

Sicurezza ed efficacia di eparina a basso peso molecolare per 72 ore seguita da dabigatran per il trattamento di embolia polmonare acuta di rischio intermedio (Pulmonary Embolism International Trial - PEITHO-2)

A.3.1

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

Safety and Efficacy of Heparin for 72 Hours Followed by Dabigatran for the Treatment of Acute Pulmonary Embolism.

Sicurezza ed efficacia di eparina a basso peso molecolare per 72 ore seguita da dabigatran per il trattamento di embolia polmonare acuta.

A.3.2

Name or abbreviated title of the trial where available

PEITHO-2

A.4.1

Sponsor's protocol code number

CTHC007

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	UNIVERSITY MEDICAL SCHOOL OF THE JOHANNES GUTENBERG UNIVERSITY MAINZ
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Boehringer Ingelheim
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Medical Center of the Johannes Gutenberg University Mainz
B.5.2	Functional name of contact point	Center for Thrombosis & Hemostasis
B.5.3	Address:
B.5.3.1	Street Address	Langenbeckstr. 1
B.5.3.2	Town/ city	Mainz
B.5.3.3	Post code	D-55131
B.5.3.4	Country	Germany
B.5.4	Telephone number	00496131178382
B.5.5	Fax number	00496131178461
B.5.6	E-mail	stavros.konstantinides@unimedizin-mainz.de

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	Yes
D.2.1.1.1	Trade name	Pradaxa 110 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Pradaxa 110 mg
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DABIGATRAN ETEXILATO
D.3.9.1	CAS number	211914-51-1
D.3.9.2	Current sponsor code	NA
D.3.9.4	EV Substance Code	SUB25417
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	110
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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	No
D.IMP: 2
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	Yes
D.2.1.1.1	Trade name	Pradaxa 150 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Pradaxa 150 mg
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DABIGATRAN ETEXILATO
D.3.9.1	CAS number	211914-51-1
D.3.9.2	Current sponsor code	NA
D.3.9.4	EV Substance Code	SUB25417
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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	No

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 Intermediate-Risk Pulmonary Embolism

Embolia Polmonare acuta a rischio intermedio

E.1.1.1

Medical condition in easily understood language

Acute Pulmonary Embolism

Embolia Polmonare Acuta

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10037379
E.1.2	Term	Pulmonary embolism and thrombosis
E.1.2	System Organ Class	100000004866

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to determine whether treatment of acute intermediate-risk PE (as defined by the inclusion and exclusion criteria) with parenteral anticoagulation for at least 72 hours after diagnosis, followed by dabigatran over 6 months, is effective and safe.

L'obiettivo primario ¿ di determinare se il trattamento dell'embolia polmonare acuta a rischio intermedio (EP) (secondo quanto definito dai criteri di inclusione ed esclusione) con anticoagulante parenterale per almeno 72 ore dopo la diagnosi, seguito da dabigatran per 6 mesi, sia efficace e sicuro

E.2.2

Secondary objectives of the trial

The secondary objective is to assess the recovery of right ventricular function over the first 6¿1 days of treatment, or upon discharge, and to evaluate its importance for the 6-months prognosis of patients with intermediate-risk PE.

L'obiettivo secondario ¿ quello di valutare il recupero della funzione ventricolare destra nel corso dei primi 6¿1 giorni di trattamento, o al momento della dimissione, e valutare la sua importanza per la prognosi a 6 mesi dei pazienti con EP a rischio intermedio

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Age =18 years;
2) Objectively confirmed diagnosis of acute PE by multidetector CT angiography, ventilation/perfusion lung scan, or selective invasive pulmonary angiography, according to established diagnostic criteria;
3) Absence of hemodynamic collapse/decompensation at presentation;
4) Intermediate-risk category of PE severity indicated by the presence of at least one of the following a, b, or c criteria:a) At least one sign of RV pressure overload/dysfunction on CT angiography or echocardiography:
a1) on CT angiography, RV pressure overload/dysfunction is defined as RV/LV end-diastolic diameter ratio >1.0; or
a2) on echocardiography, RV pressure overload/dysfunction is defined by the presence of at least one of the following findings:
• RV/LV end-diastolic diameter ratio >1.0 (apical or subcostal 4-chamber view);
• RV end-diastolic diameter >30 mm (parasternal long-axis or short-axis view);
• RV free wall hypokinesis (any view);
• Tricuspid regurgitant jet velocity >2.6 m/s from the apical or subcostal 4-chamber view, or the parasternal short-axis view;
• Absence of inspiratory collapse of the inferior vena cava.
b) Signs of myocardial injury as indicated by elevated troponin levels:
• Troponin elevation is defined as an abnormal result of any validated troponin test based on the reference values determined by the local Department of Clinical Chemistry at each participating site;
c) Signs of (RV) failure as indicated by NT-proBNP levels >600 pg/ml
5) Signed and dated informed consent of the subject available.

1) Età = 18 anni;
2) Diagnosi obiettivamente confermata di EP acuta mediante angiografia TC multidetector, scansione polmonare con ventilazione/perfusione, o angiografia polmonare invasiva selettiva, secondo i criteri diagnostici stabiliti;
3) Assenza di collasso emodinamico/scompenso alla presentazione;
4) Categoria di rischio intermedio di gravità EP indicato dalla presenza di almeno uno dei seguenti criteri a, b, o c:
a) Almeno un segno di sovraccarico/disfunzione della pressione RV all'angiografia TC o ecocardiografia (8,23):
a1) all'angiografia TC, il sovraccarico/disfunzione della pressione RV è definito come il rapporto del diametro telediastolico RV/LV > 1,0; o
a2) all'ecocardiografia, il sovraccarico/disfunzione della pressione RV è definito dalla presenza di almeno uno uno dei seguenti riscontri:
• rapporto diametro telediastolico RV/LV- >1,0 (vista apicale o sottocostale 4-camere);
• rapporto diametro telediastolico RV-> 30 mm (vista parasternale asse lungo o asse corto);
• ipocinesia della parete RV (qualsiasi vista);
• velocità del getto di rigurgito tricuspidale > 2,6 m/s dalla vista apicale o sottocostale 4-camere, o vista parasternale asse corto;
• Assenza di collasso inspiratorio della vena cava inferiore.
b) Segni di danno miocardico, secondo quanto indicato da livelli di troponina elevati:
• L'elevazione della troponina è definita come un risultato anomalo di qualsiasi esame della troponina convalidato in base ai valori di riferimento determinati dal locale Dipartimento di Chimica Clinica presso ciascun centro partecipante;
c) Segni di insufficienza (RV), secondo quanto indicato da livelli di NT-proBNP> 600 pg/ml
5) Disponibilità del consenso informato firmato e datato del soggetto.

E.4

Principal exclusion criteria

1) Pregnancy or women of childbearing potential who do not practice a medically accepted highly effective contraception during the trial and one month beyond;
2) Use of a fibrinolytic agent, surgical thrombectomy, interventional (catheter-directed) thrombus aspiration or lysis, or use of a cava filter to treat the index episode of PE;
3) Need for long-term treatment with a low molecular weight heparin, a vitamin K antagonists, or a new oral anticoagulant (rivaroxaban, dabigatran, apixaban or edoxaban), for an indication other than the index PE episode; or for antiplatelet agents except a etylsalicylic acid at a dosage =100 mg/day;
4) Active bleeding or known significant bleeding risk;
5) Renal insufficiency with estimated creatinine clearance <30 ml/min/1.73m2;
6) Non-compliance or inability to adhere to treatment or to the follow-up visits;
7) Life expectancy less than 6 months.

1) Donne gravide o potenzialmente fertili che non praticano contraccezione altamente efficace accettata dal punto di vista medico durante la sperimentazione e per un mese successivo;
2) Uso di un agente fibrinolitico, trombectomia chirurgica, trombo-aspirazione o lisi interventistica (catetere-guidata), o uso di un filtro cava per trattare l'episodio indice di EP;
3) Necessità di un trattamento a lungo termine con un'eparina a basso peso molecolare, antagonisti della vitamina K, o un nuovo anticoagulante orale (rivaroxaban, dabigatran, apixaban o edoxaban), per un'indicazione diversa dalla VTE; o di agenti antipiastrinici, tranne l'acido acetilsalicilico a dosaggio =100 mg/die;
4) Sanguinamento attivo o significativo rischio emorragico noto;
5) Insufficienza renale con clearance della creatinina stimata <30 ml/min/1,73 m2;
6) Mancato rispetto o impossibilità di osservare il trattamento o le visite di follow-up;
7) Aspettativa di vita inferiore a 6 mesi.

E.5 End points

E.5.1

Primary end point(s)

The primary outcome is whether symptomatic VTE or EP-related death occurs within the first 6 months of anticoagulant therapy (yes/no(. Symptomatic VTE or EP-related death are defined in chapter 2.2 of the Protocol

l'outcome primario è se il decesso sintmatico VTE o EP- correlato si verifica entro i primi 6 mesi di terapia anticoagulante (si/no). Il decesso sintomatico VTE o EP-correlato è definito nel capitolo 2.2 del Protocollo.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months after anticoagulation therapy

6 mesi dopo la terapia anticoagulante

E.5.2

Secondary end point(s)

1) Recovery or RV function at 6¿1 days after PE diagnosis or upon discharge (wichever comes first) and at 6-month follow-up, as assessed by echocardiography;
2) Course of NT-proBNP levels during follow-up (measurement at baseline, 6¿1 days or at discharge, and 6-month follow-up);
3) Death from any cause, or hemodynamic collapse or decompensation, within the first 30 days;
4) PE-related death, or PE-related hemodynamic collapse or decompensation, within the forst 30 days;
5) Overall duration of hospital stay (index event and repeated hospitalizations due to PE [index or recurrent event] or to a bleeding event) within 6 months;
6) Death from any cause within 6 months.

1) Recupero della funzione RV a 6¿1 giorni dopo la diagnosi di EP o alla dimissione (l'evento che si verifica prima) e al follow-up di 6 mesi, valutato mediante ecocardiografia;
2) Decorso dei livelli di NT-proBNP durante il follow-up (misurazione al basale, 6¿1 giorni o al momento della dimissione, e al follow-up di 6 mesi);
3) Decesso per qualsiasi causa, o collasso emodinamico o scompenso, entro i primi 30 giorni;
4) Decesso EP-correlato, o collasso emodinamico o scompenso EP-correlato, entro i primi 30 giorni;
5) Durata complessiva della degenza ospedaliera (evento indice e ricoveri ripetuti a causa di EP [indice o evento ricorrente] o ad un evento emorragico) entro 6 mesi;
6) Decesso per qualsiasi causa entro 6 mesi.

E.5.2.1

Timepoint(s) of evaluation of this end point

30 days, 6 months after PE diagnosis

30 giorni, 6 mesi dopo la diagnosi di EP

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

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

Israel

Serbia

Austria

Belgium

France

Germany

Italy

Netherlands

Poland

Romania

Slovenia

Spain

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

Last patient last visit (LPLV)

Ultimo paziente ultima visita

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

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)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

500

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

200

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

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

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

150

F.4.2

For a multinational trial

F.4.2.1

In the EEA

510

F.4.2.2

In the whole clinical trial

530

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)

Dabigatran as study medication will be taken for a period of 6 months. After that period continuation of anticoagulation and the anticoagulant drug to be used will be at the discretion of the patient¿s physician.

Dabigatran come farmaco in studio verr¿ assunto per un periodo di 6 mesi. Dopo tale periodo la continuazione della terapia anticoagulante e il farmaco anticoagulante da utilizzare sar¿ a discrezione del medico del paziente.

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

2016-12-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-12-13

P. End of Trial
P.	End of Trial Status	Completed

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