Clinical Trials Register

Summary
EudraCT Number:	2008-006441-10
Sponsor's Protocol Code Number:	116-02
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-12-09
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

Austria - BASG

A.2

EudraCT number

2008-006441-10

A.3

Full title of the trial

A double blind controlled clinical study to investigate the efficacy and tolerability of subcutaneous Treprostinil sodium in patients with severe non-operable Chronic Thromboembolic Pulmonary Hypertension (CTREPH II)

PROSPEKTIVE, RANDOMISIERTE, KONTROLLIERTE, DOPPELBLINDE, MULTIZENTRISCHE PARALLELGRUPPENSTUDIE ZUR UNTERSUCHUNG VON WIRKSAMKEIT, SICHERHEIT UND VERTRÄGLICHKEIT VON SUBKUTANEM TREPROSTINIL BEI PATIENTEN MIT INOPERABLER CHRONISCHER THROMBOEMBOLISCHER PULMONALER HYPERTENSION (CTREPH).

A.3.1

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

Study to evaluate the efficacy and safety of Treprostinil which will be
continuously administered under the skin by patients with inoperable
Chronic Thromboembolic Pulmonary Hypertension.

Studie zur Untersuchung der Wirksamkeit und Sicherheit von Treprostinil, das kontinuierlich unter die Haut bei Patienten mit inoperabler chronischer thromboembolischer pulmonarer Hypertension injiziert wird.

A.3.2

Name or abbreviated title of the trial where available

CTREPH

A.4.1

Sponsor's protocol code number

116-02

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	SCIPHARM SáRL
B.1.3.4	Country	Luxembourg
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	Yes
D.2.5.1	Orphan drug designation number	EU/3/13/1103
D.3 Description of the IMP
D.3.1	Product name	Treprostinil Sodium
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Treprostinil
D.3.9.1	CAS number	289480644
D.3.9.3	Other descriptive name	TREPROSTINIL SODIUM
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Treprostinil
D.3.9.1	CAS number	289480644
D.3.9.3	Other descriptive name	TREPROSTINIL SODIUM
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	2,5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Treprostinil
D.3.9.1	CAS number	289480644
D.3.9.3	Other descriptive name	TREPROSTINIL SODIUM
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	5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Treprostinil
D.3.9.1	CAS number	289480644
D.3.9.3	Other descriptive name	TREPROSTINIL SODIUM
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	10
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	Yes
D.3.11.13.1	Other medicinal product type	Prostacycline Analogue
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/13/1103
D.3 Description of the IMP
D.3.1	Product name	Treprostinil Sodium
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Treprostinil
D.3.9.1	CAS number	289480644
D.3.9.3	Other descriptive name	TREPROSTINIL SODIUM
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	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	Yes
D.3.11.13.1	Other medicinal product type	Prostacycline Analogue

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

Patients with Severe (inoperable) Chronic Thromboembolic Pulmonary Hypertension

E.1.1.1

Medical condition in easily understood language

(CTEPH) is characterized by non‐resolving organized thromboemboli obstructing the pulmonary vascular bed. These thrombi are resistant to thrombolytic therapy and chronic plasmatic anticoagulation.

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the effect of subcutaneous Treprostinil sodium on 6MWT
distance after 24 weeks in patients with severe non-operable chronic
thromboembolic pulmonary hypertension

E.2.2

Secondary objectives of the trial

1. To assess clinical worsening defined as a decrease of
6MWT distance of more than 20% from baseline due to CTEPH, as
decrease of NYHA functional class, hospitalization with the requirement
for additional PH specific treatment and/or death due to worsening
CTEPH
2. To assess the effect on maximal Borg score, heart rate and oxygen
saturation during 6MWT
3. To assess the effect on WHO NYHA functional class
4. To assess the effect on QOL by the MINNESOTA instrument

Exploratory analyses:
1. To assess the effect on pro-BNP levels
2. To assess the effect on hemodynamic parameters
3. To assess the effect on signs & symptoms

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.
Subject must be competent to understand the information given in the written informed consent and from the investigator and must sign and date the informed consent prior to any study mandated procedure.
2.
Subject must be at least 18 years of age and could be of any ethnical origin
3.
Women of child bearing potential must be surgically sterile or postmenopausal (amenorrhea for at least 12 months) or using an acceptable form of contraception. Reliable contraception is defined as a method which results in a low failure rate, i.e., less than 1% per year when used correctly such as, implants, injectables, oral contraceptive medications, sexual abstinence, or a vasectomised partner.
4.
Subject must have a current diagnosis of CTEPH, as defined by the following criteria:
•
A test result of perfusion scintigraphy and pulmonary angiography and/or multislice CT not older than 6 months, consistent with the diagnosis CTEPH. In case of recurrent PH after PEA, test results from before the surgery are acceptable if a typical specimen was harvested during PEA substantiating the diagnosis of CTEPH.
•
A right heart catheterization, not older than 6 months, consistent with the diagnosis CTEPH but specifically with a PAPm of > 25 mmHg, and a PVR of > 300 dyn.s.cm‐5
•
At least three months of effective anticoagulation therapy (without improvement/to exclude subacute pulmonary emboli)
5.
Subject must have a CTEPH classified as severe, as defined by the following criteria:
•
An un‐encouraged 6MWT of between 150 and 400 meters
•
Classification in the WHO/NYHA functional class III or IV
6.
The subject must not be suitable to undergo a PEA and is therefore defined as non‐operable, due to at least one of the following reasons:
•
Clot is not accessible
•
Discrepancy between severity of PH and morphologic lesion
•
Subject is not a good surgical candidate for other reasons:
��
PVR > 1500 dynes.s.cm‐5
��
Age
��
Comorbidity
��
No functional lung parenchyma
•
Unsuccessful PEA in the past with residual/recurrent CTEPH
•
No consent for PEA given by the patient
7.
Subject must be willing and able to follow all study procedures

E.4

Principal exclusion criteria

1.
Subject with any form of pulmonary arterial hypertension or any disease known to cause PAH (WHO Group I)
2.
Subjects with a total lung capacity (TLC) of < 70% predicted or a forced expiratory volume/forced capacity (FEV1/FVC < 50%)
3.
Subject who received any prostanoids, within the 30 days before screening or be scheduled to receive prostanoids during the course of the study
4.
Subject with a new type of chronic therapy (a different category of vasodilator or diuretic) for
PAH added within the last month, except anticoagulants
5.
Subject with an increased risk for hemorrhage or stroke or with a major cardiovascular event during the past 6 months.
6.
Unstable subjects for any reason (according to the investigators discretion)
7.
Subject who received any investigational medication within 30 days prior to the screening visit of this study or be scheduled to receive another investigational drug during the course of this study
8.
Subject with a known intolerance to any drug, relevant for this study especially to Treprostinil sodium or prostanoids
9.
Subject with a history or suspicion of non compliance
10.
Have any musculoskeletal disease or any other disease that would limit ambulation
11.
Subject with other cardiovascular, liver, renal, hematologic, gastrointestinal immunologic, endocrine, metabolic, or central nervous system disease that, in the opinion of the investigator, may adversely affect the safety of the subject and /or efficacy of the study drug or limit the lifespan of the subject
12.
Female who is considering pregnancy or who is pregnant and/or lactating
13.
Subject who is an investigator or any other team member involved directly or indirectly in the conduct of the clinical study.
14.
Subject who is an inmate of a psychiatric ward, prison or is suspected not to be able to give consent of his free will

E.5 End points

E.5.1

Primary end point(s)

Change in 6MWT distance after 24 weeks

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline, Visit 4 (week 12), Visit 6 (week 24)

E.5.2

Secondary end point(s)

1. Clinical worsening defined as a decrease of 6MWT distance of
more than 20% from baseline due to CTEPH, decrease of NYHA
functional class, hospitalization with the requirement for additional PH
specific treatment and/or death due to worsening CTEPH
2. Change in 6 MWT after 12 weeks
3. Change in maximal Borg score, heart rate and oxygen saturation
during 6MWT
4. Change in WHO functional class
5. Change in MINNESOTA QOL instrument

Exploratory:
1. Change in pro-BNP levels after 24 weeks
2. Change in hemodynamic parameters
3. Change in signs & symptoms

E.5.2.1

Timepoint(s) of evaluation of this end point

1. troughout the trial
2. Baseline, Visit 4 (12 weeks), Visit 6 (24 weeks)
3. Baseline, Visit 4 (12 weeks), Visit 6 (24 weeks)
4. Baseline, Visit 4 (12 weeks), Visit 6 (24 weeks)
5. Baseline, Visit 4 (12 weeks), Visit 6 (24 weeks)

Exploratory:
1. Baseline, Visit 6 (24 weeks)
2. Baseline, Visit 6 (24 weeks)
3. Baseline, Visit 4 (12 weeks), Visit 6 (24 weeks)

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

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)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

Yes

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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.7

Trial has a data monitoring committee

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 blinded study phase

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

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

100

F.4.2.2

In the whole clinical trial

100

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)

Patients will receive a follow up treatment according to the investigators opinion.

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

2009-06-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-11-04

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-04-09

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