Clinical Trials Register

Summary
EudraCT Number:	2018-002823-41
Sponsor's Protocol Code Number:	AC-065B302
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-11-01
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

Czechia - SUKL

A.2

EudraCT number

2018-002823-41

A.3

Full title of the trial

A multicenter, randomized, double-blind, placebo-controlled, parallel-group, group-sequential, adaptive, Phase 3 study with open-label extension period to assess the efficacy and safety of selexipag as an add-on to standard of care therapy in subjects with inoperable or persistent/recurrent after surgical and/or interventional treatment Chronic Thromboembolic Pulmonary Hypertension.

Multicentrická, randomizovaná, dvojitě zaslepená, placebem kontrolovaná studie fáze 3, prováděná v paralelních skupinách, se sekvenčním, adaptivním designem a s otevřeným prodloužením léčby k posouzení účinnosti a bezpečnosti selexipagu přidaného ke standardní léčbě u pacientů s neoperovatelnou nebo po chirurgické a/nebo intervenční léčbě perzistující/rekurentní chronickou tromboembolickou plicní hypertenzí (CTEPH)

A.3.1

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

A clinical study to assess the efficacy and safety of selexipag as an add-on to standard of care therapy in subjects with inoperable or persistent/recurrent, after surgical treatment and/or Chronic Thromboembolic Pulmonary Hypertension (CTEPH).

A.3.2

Name or abbreviated title of the trial where available

SELECT

A.4.1

Sponsor's protocol code number

AC-065B302

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	Actelion Pharmaceuticals Ltd
B.1.3.4	Country	Switzerland
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	Actelion Pharmaceuticals Ltd
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Janssen-Cilag International NV
B.5.2	Functional name of contact point	Clinical Registry group
B.5.3	Address:
B.5.3.1	Street Address	Archimedesweg 29
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333 CM
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31715242166
B.5.5	Fax number	+31715242110
B.5.6	E-mail	clinicalTrialsEU@its.jnj.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	Yes
D.2.1.1.1	Trade name	Uptravi
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen-Cilag International NV
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	Selexipag
D.3.2	Product code	ACT-293987
D.3.4	Pharmaceutical form	Film-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	SELEXIPAG
D.3.9.2	Current sponsor code	ACT-293987
D.3.9.4	EV Substance Code	SUB130805
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic Thromboembolic Pulmonary Hypertension, inoperable or persistent/recurrent

E.1.1.1

Medical condition in easily understood language

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a disease associated with abnormally high pressure in the blood vessels of the lungs, caused by the formation of blood clots.

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	LLT
E.1.2	Classification code	10068739
E.1.2	Term	Chronic thromboembolic pulmonary hypertension
E.1.2	System Organ Class	100000004855

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

The primary objective of the study is to evaluate the effect of selexipag on pulmonary vascular resistance (PVR) versus placebo in subjects with inoperable CTEPH (i.e., technically non-operable) and persistent/recurrent CTEPH after surgical treatment (pulmonary endarterectomy [PEA] and/or interventional (balloon pulmonary angioplasty [BPA]) treatment at Week 20.

E.2.2

Secondary objectives of the trial

The secondary objectives of the study are to evaluate the effects of selexipag versus placebo on:
• Exercise capacity
• Time to clinical worsening (TTCW)
• All-cause death or hospitalization related to PH worsening
• WHO functional class (FC)
• Patient-reported outcomes (PROs)
• Dyspnea
• N-terminal pro b-type natriuretic peptide (NT-proBNP).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed and dated ICF.
2. Male and female subjects ≥18 (or the legal age of consent in the jurisdiction in which the study is taking place) and ≤ 85 years old at Screening (Visit 1).
3. Subjects with diagnosis of CTEPH and inoperabillity confirmed by the corresponding adjudication committee (AC; country-specific adjudication committee [CSAC] or central adjudication committee [CAC]), defined as one of the following options:
a) Inoperable CTEPH (i.e., technically non-operable) with:
– Diagnosis of CTEPH based on at least two of the following assessments performed in the 14-month period prior to randomization (Visit 2): ventilation/perfusion (V/Q) scan; pulmonary angiography (PA); computed tomography pulmonary angiogram (CTPA) and/or magnetic resonance angiography (MRA).
– RHC (and LHC, if needed) 1 performed at least 90 days after start of full anticoagulation showing: PVR at rest ≥ 400 dyn.sec/cm5 or ≥ 5 Wood units for the hemodynamic cohort and PVR at rest ≥ 300 dyn.sec/cm5 or ≥ 3,75 Wood units for the non-he,odynamic cohort; Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg; Pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg or, if not available or unreliable, a left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg.
b) Persistent/recurrent CTEPH after BPA, with:
– Diagnosis of CTEPH based on at least one of the following assessments performed in the 14-month period prior to randomization (Visit 2) and after last interventional (BPA) treatment: V/Q scan, PA, CTPA or MRA.
– RHC (and LHC, if needed) 1 performed at least 90 days after last interventional (BPA) treatment and at least 90 days after start of full anticoagulation showing: PVR at rest ≥ 400 dyn.sec/cm5 or ≥ 5 Wood units for the hemodynamic cohort and PVR at rest ≥ 300 dyn.sec/cm5 or ≥ 3,75 Wood units for the non-he,odynamic cohort ; mPAP ≥ 25 mmHg; PAWP ≤ 15 mmHg, or, if not available or unreliable, an LVEDP ≤ 15 mmHg.
c) Persistent/recurrent CTEPH after PEA (including PEA followed by BPA) with:
-– Diagnosis of CTEPH based on at least one of the following assessments performed in the 14-month period prior to randomization (Visit 2) and after last surgical (PEA) or interventional (BPA) treatment: V/Q scan, PA, CTPA or MRA.
– RHC (and LHC, if needed) 1 performed at least 90 days after last surgical (PEA) or interventional (BPA) treatment and at least 90 days after start of full anticoagulation showing: PVR at rest ≥ 400 dyn.sec/cm5 or or 5 Wood units for the hemodynamic cohort and PVR at rest ≥ 300 dyn.sec/cm5 or ≥ 3,75 Wood units for the non-he,odynamic cohort; mPAP ≥ 25 mmHg; PAWP ≤ 15 mmHg, or, if not available or unreliable, an LVEDP ≤ 15 mmHg.
4. Symptomatic PH in WHO FC I–IV.
5. Subject able to perform the 6MWT with a minimum distance of 100 m and a maximum distance of 450 m at screening visit (Visit 1).

E.4

Principal exclusion criteria

General exclusion criteria:
1. Planned or current treatment with another investigational treatment up to 3 months prior to randomization.
2. Any known factor or disease that might interfere with treatment compliance, study conduct, or interpretation of the results, such as drug or alcohol dependence or psychiatric disease.
3. Known concomitant life-threatening disease with a life expectancy < 12 months.

Exclusion criteria related to the disease:
4. Planned BPA within 26 weeks after randomization.
5. Change in dose or initiation of new PH-specific therapy within 90 days prior to yhe baseline RHC (and LHC, if needed) qualifying for enrollment for the hemodynamic cohort and within 90 days prior to randomization (Visit 2) for the non-hemodynamic cohort.
6. Treatment with prostacyclin (epoprostenol), prostacyclin analogs (i.e., treprostinil, iloprost, beraprost) or prostacyclin receptor agonists (i.e., selexipag/Uptravi) within 90 days prior to randomization (Visit 2), except those given at vasodilator testing during RHC.
7. Change in dose or initiation of new diuretics and/or calcium channel blockers within 1 week prior to baseline RHC (and LHC, if needed).

Exclusion criteria related to comorbidities:
8. Any co-morbid condition that may influence the ability to perform a reliable and reproducible 6MWT, including use of walking aids (cane, walker, etc).
9. Other as per selexipag Summary of Product Characteristics (SmPC).

Exclusion criteria related to selexipag use:
10. As per selexipag Summary of Product Characteristics (SmPC).

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint of this study is the pulmonary vascular resistance (PVR) at Week 20, assessed at rest, within 2–5 hours post-dose, expressed as percent of baseline PVR.

E.5.1.1

Timepoint(s) of evaluation of this end point

Assessed at rest in screening period (Day -60 to Day -14; baseline) and assessed at rest within 2–5 hours post-dose at Week 20 during treatment period.

E.5.2

Secondary end point(s)

1. Change from baseline in 6-minute walk distance (6MWD) to Week 26 (key secondary endpoint).
2. Time to clinical worsening (according to the CHMP definition, key secondary endpoint), defined as at least one of the following components confirmed by the CEC, when applicable:
– All-cause death
– Non-planned PH-related hospitalization
– PH-related deterioration identified by at least one of the following: Increase from baseline in WHO FC4; Deterioration by at least 15% in exercise capacity, as measured by the 6MWD4; New signs or symptoms of right heart failure, defined as a reported AE with one of the preferred terms "CTEPH”, “pulmonary hypertension”, “right ventricular failure”, “right ventricular dysfunction” and/or “acute right ventricular failure”).
The investigation of a composite endpoint that reflects the TTCW has been encouraged by the European Medicines Agency.
3. All-cause death or hospitalization related to PH worsening
4. Proportion of subjects with improvement in WHO FC from baseline to Week 26.
5. Change from baseline to Week 26 in PAH-SYMPACT™ cardiopulmonary symptom domain and crdiovascular symptom domain..
6. Change from baseline to Week 26 in Borg dyspnea index (BDI)/Borg CR10.
7. Change from baseline to Week 26 in NT-proBNP.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Week 26
2. end of double blind treatment period
3. end of double blind treatment period
4. Week 26
5. Week 26
6. Week 26
7. Week 26

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

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

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

Yes

E.8.1.7.1

Other trial design description

Group-sequential

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

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

Yes

E.8.4

The trial involves multiple sites in the 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

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

Argentina

Australia

Austria

Belgium

Brazil

Bulgaria

Canada

China

Czech Republic

Denmark

Finland

Germany

Hungary

Israel

Italy

Korea, Republic of

Mexico

Netherlands

Poland

Portugal

Russian Federation

Slovakia

South Africa

Spain

Sweden

Switzerland

Taiwan

Thailand

Turkey

Ukraine

United Kingdom

United States

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero