Clinical Trials Register

Summary
EudraCT Number:	2013-001657-28
Sponsor's Protocol Code Number:	CTHC002
National Competent Authority:	Finland - Fimea
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-08-24
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

Finland - Fimea

A.2

EudraCT number

2013-001657-28

A.3

Full title of the trial

Home Treatment of Patients with Low-Risk Pulmonary Embolism with the Oral Factor Xa Inhibitor Rivaroxaban: Prospective Management Trial (HoT-PE)

A.3.1

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

Home Treatment of Patients with Low-Risk Pulmonary Embolism with Rivaroxaban

A.3.2

Name or abbreviated title of the trial where available

HoT-PE

A.4.1

Sponsor's protocol code number

CTHC002

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 Center 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	Bayer Pharma AG
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	Prof. Dr. S. Konstantinides
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	Xarelto 15 mg Filmtabletten
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Pharma AG
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	Xarelto 15 mg Filmtabletten
D.3.2	Product code	B01AF01
D.3.4	Pharmaceutical form	Coated tablet
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	RIVAROXABAN
D.3.9.1	CAS number	366789-02-8
D.3.9.4	EV Substance Code	SUB29263
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	15
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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	Xarelto 20 mg Filmtabletten
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Pharma AG
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	Xarelto 20 mg Filmtabletten
D.3.2	Product code	B01AF01
D.3.4	Pharmaceutical form	Coated tablet
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	RIVAROXABAN
D.3.9.1	CAS number	366789-02-8
D.3.9.4	EV Substance Code	SUB29263
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	20
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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 low-risk pulmonary embolism (PE)

E.1.1.1

Medical condition in easily understood language

Acute low-risk pulmonary embolism

Akuutti matalan riskin keuhkoembolia

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	19.0
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

To determine whether early discharge and out-of-hospital treatment of patients with low-risk acute PE (as defined by the inclusion and exclusion criteria) with the new oral factor Xa inhibitor rivaroxaban is feasible, effective, and safe.

E.2.2

Secondary objectives of the trial

-To determine whether early discharge and out-of-hospital treatment of low-risk acute PE with the new oral factor Xa inhibitor rivaroxaban can result in good quality of life and patient satisfaction
-To obtain valid health economic variables as a basis for description of resource utilization, including validation of a disease-specific quality of life questionnaire, and of existing Markov models.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Age ≥18 years;
2) Ability of subject to understand character and individual consequences of clinical trial;
3) Signed and dated informed consent of the subject available before the start of any specific trial procedures;
4) Women of childbearing potential have to practice a medically accepted contraception (non-hormonal intrauterine device, two independent barriers, female or male surgical sterilization, or two years postmeno-pausal) during the trial, and a negative pregnancy test (serum or urine) should be available before inclusion in the trial;
5) Objectively confirmed diagnosis of acute PE by multidetector computed tomographic (CT) pulmonary angiography, pulmonary angiography, or V/Q lung scan according to established diagnostic criteria, with or without symptomatic deep vein thrombosis;
6) Absence of right ventricular (RV) enlargement or dysfunction, and of free floating thrombi
in the right atrium or right ventricle on echocardiography or computed tomography.
On echocardiography, RV enlargement/dysfunction is absent when both criteria listed
below are met:
- Right/left ventricular end-diastolic diameter ratio < 0.9 (apical or subcostal 4-chamber
view)
- No paradoxical motion of the interventricular septum
On CT angiography, RV enlargement/dysfunction is absent when the following criterion is
met:
- Right/left short-axis diameter ratio < 0.9 (transverse plane)

E.4

Principal exclusion criteria

-Hemodynamic instability at presentation, indicated by at least one of the following: (i) systolic blood pressure (SBP) < 100 mm Hg, or heart rate >100 beats per minute, or SBP drop by > 40 mm Hg, for > 15 min; (ii) need for catecholamines to maintain adequate organ perfusion and a systolic blood pressure of >100 mm Hg; (iii) need for cardiopulmonary resuscitation;
-Right ventricular (RV) enlargement or dysfunction, or free floating thrombi in the right atrium or right ventricle, detected by echocardiography or computed tomography;
-Treatment with low-molecular-weight heparin, fondaparinux, or unfractionated heparin for more than 48 hours, or more than a single dose of a vitamin K antagonist prior to inclusion in the study;
-Treatment with rivaroxaban, dabigatran, apixaban, edoxaban or any other new generation antithrombotics on admission;
-Use of a fibrinolytic agent, surgical thrombectomy, interventional (transcatheter) thrombus aspiration or lysis, or use of a cava filter to treat the index episode of PE;
- Need for supplemental oxygen administration to maintain oxygen saturation >90%;
-Pain requiring parenteral administration of analgesic agents;
-Other medical conditions/comorbidities requiring hospitalization;
- Acute PE diagnosed in a patient already hospitalized for another condition;
- Pregnancy or lactation;
- Active bleeding or known significant bleeding risk;
-Severe renal insufficiency (estimated GFR <15 ml/min/1.73m2) or end-stage renal disease;
-Severe hepatic failure;
-Known allergy or intolerance to rivaroxaban;
-Concomitant administration of strong inhibitors of P-gp and CYP3A4 such as azole antimycotic agents or HIV protease inhibitors;
-Need for long-term treatment vitamin K antagonists, or for antiplatelet agents except acetylsalicylic acid at a dosage <100 mg/day;
-Non-compliance or inability to adhere to treatment or to the follow-up visits; or lack of a family environment or support system for home treatment;
-Life expectancy less than 3 months.

E.5 End points

E.5.1

Primary end point(s)

Symptomatic recurrent venous thromboembolism (VTE) or death related to pulmonary embolism

E.5.1.1

Timepoint(s) of evaluation of this end point

within 3 months after enrolment

E.5.2

Secondary end point(s)

- All-cause mortality within 7 days;
- All-cause mortality within 3 weeks;
- All-cause mortality within 3 months;
- Overall duration of hospital stay (index event and repeated hospitalizations due to PE
[index or recurrent event] or to a bleeding event) within 3 months;
- Rehospitalization due to PE (index or recurrent event) or to a bleeding event within 3
months;
- Generic and disease-specific quality of life at baseline, 1 week, 3 weeks, and 3 months;
- Treatment satisfaction at 3 weeks and 3 months;
- Utilization of health care resources at 3 weeks and 3 months;
- All-cause mortality at one year.
Safety outcomes:
- Major bleeding, based on the ISTH definition, within 7 days, 3 weeks, and 3 months;
- Clinically relevant bleeding, defined as a composite of major or clinically relevant non-
major bleeding, within 7 days, 3 weeks, and 3 months;
- Serious adverse events (SAE) within 7 days, 3 weeks, and 3 months.

E.5.2.1

Timepoint(s) of evaluation of this end point

7 days, 3 weeks, and 3 months

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

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

Yes

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.8.3

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

E.8.6.2

Trial being conducted completely outside of the EEA

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 visit last subject

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:

800

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

300

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1100

F.4.2.2

In the whole clinical trial

1100

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)

Rivaroxaban as study medication will be taken for a period of 3 months. After that period continuation of anticoagulation and the anticoagulant drug to be used will be at the discretion of the patient’s physician.

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

2016-09-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-08-31

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-11-26

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