Clinical Trials Register

Summary
EudraCT Number:	2019-004131-24
Sponsor's Protocol Code Number:	67896062CTP3001
National Competent Authority:	Lithuania - SMCA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-09-22
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

Lithuania - SMCA

A.2

EudraCT number

2019-004131-24

A.3

Full title of the trial

A prospective, randomized, double-blind, multicenter, placebo-controlled, parallel group, adaptive Phase 3 study with open-label extension to evaluate efficacy and safety of macitentan 75 mg in inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension.

Macitentan in inoperAble or persistent/reCurrent chronIc ThromboEmbolic Pulmonary Hypertension (MACiTEPH)

A.3.1

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

A Phase 3 study to evaluate whether macitentan 75 mg is an effective and safe treatment for patients with inoperable or persistent chronic thromboembolic pulmonary hypertension.

A.3.2

Name or abbreviated title of the trial where available

MACiTEPH

A.4.1

Sponsor's protocol code number

67896062CTP3001

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	+3171 5242166
B.5.5	Fax number	+3171 5242110
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	Opsumit®
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	Macitentan tablets
D.3.2	Product code	JNJ-67896062 / ACT-064992
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	MACITENTAN
D.3.9.1	CAS number	441798-33-0
D.3.9.2	Current sponsor code	JNJ-67896062-AAA
D.3.9.3	Other descriptive name	ACT-064992
D.3.9.4	EV Substance Code	SUB89247
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	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	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	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	Macitentan tablets
D.3.2	Product code	JNJ-67896062 / ACT-064992
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	MACITENTAN
D.3.9.1	CAS number	441798-33-0
D.3.9.2	Current sponsor code	JNJ-67896062-AAA
D.3.9.3	Other descriptive name	ACT-064992
D.3.9.4	EV Substance Code	SUB89247
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	75
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: 3
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	Macitentan tablets
D.3.2	Product code	JNJ-67896062 / ACT-064992
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	MACITENTAN
D.3.9.1	CAS number	441798-33-0
D.3.9.2	Current sponsor code	JNJ-67896062-AAA
D.3.9.3	Other descriptive name	ACT-064992
D.3.9.4	EV Substance Code	SUB89247
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	37.5
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
D.8 Placebo: 2
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
D.8 Placebo: 3
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

E.1.1.1

Medical condition in easily understood language

CTEPH is a rare type of pulmonary hypertension, a condition in which the pressure in the blood vessels going to the lungs (pulmonary arteries) is higher than normal due to restricted blood flow.

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10064911
E.1.2	Term	Pulmonary arterial hypertension
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

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 evaluate the effect of macitentan 75 mg versus placebo on exercise capacity at Week 28 in participants with chronic thromboembolic pulmonary hypertension (CTEPH).

E.2.2

Secondary objectives of the trial

• To evaluate the effect of macitentan 75 mg versus placebo on time to clinical worsening up to EODBT.
• To evaluate the effect of macitentan 75 mg versus placebo on WHO FC at Week 28.
• To evaluate the effect of macitentan 75 mg versus placebo on quality of life at Week 28.
• To evaluate the effect of macitentan 75 mg versus placebo on daily physical activity.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

• The objective of this sub-study is to confirm the effect of macitentan 75 mg versus placebo on PVR in participants with inoperable or persistent/recurrent CTEPH.
• Patients participating in the substudy will undergo RHC at Screening and at Week 28.
• The RHC will only be performed at sites able to comply with the protocol-specific RHC guidelines.

E.3

Principal inclusion criteria

• Male or female ≥ 18 (or the legal age of consent in the jurisdiction in which the study is taking place)and ≤80 years of age.
• CTEPH (WHO Group 4) fulfilling one of the following criteria:
a. Inoperable due to the localization of the obstruction being surgically inaccessible (ie, distal disease) as confirmed by the adjudication committee (AC), and diagnosed based on
• At least 2 of the following assessments in the 14 month-period prior to Randomization: Ventilation / Perfusion (V/Q) scan, pulmonary angiography (PA), computed tomography pulmonary angiogram (CTPA), magnetic resonance angiography (MRA).
- RHC at least 12 weeks after full anticoagulation showing the following (at Screening or in the 24 week period prior to Randomization): mPAP > 20 mmHg, PAWP ≤15 mmHg and PVR ≥240 dyn·sec/cm5.
b. Persistent/recurrent CTEPH after BPA, and deemed inoperable due to the localization of the obstruction being surgically inaccessible (ie, distal disease) as confirmed by the AC, diagnosed based on:
• At least one of the following assessments performed after the latest BPA in the 14-month period prior to Randomization: V/Q scan, PA, CTPA or MRA
• RHC at least 12 weeks after BPA and full anticoagulation showing the following (at Screening or in the 24-week period prior to Randomization): mPAP > 20 mmHg, PAWP ≤15 mmHg and PVR≥240 dyn·sec/cm5.
c. Persistent/recurrent CTEPH after PEA (including PEA followed by BPA), diagnosed based on:
• At least one of the following assessments performed after the PEA (and latest BPA following PEA, if applicable) in the 14-month period prior to Randomization: V/Q scan, PA, CTPA or MRA.
• RHC performed at least 12 weeks after PEA (or latest BPA, if applicable) and full anticoagulationa showing the following (at Screening or in the 24 week period prior to Randomization): mPAP > 20 mmHg, PAWP ≤15 mmHg and PVR≥240 dyn·sec/cm5.
• 6MWD ≥ 100 m AND ≤ 450 m, documented by an eligibility and a baseline 6MWT. The baseline 6MWD must not differ by more than 15% from the eligibility test.
• WHO FC ≥II.
• Participants are to receive riociguat as per local standard of care, unless it is contraindicated or unavailable

E.4

Principal exclusion criteria

• Acute pulmonary embolism within 3 months prior to or during
Screening.
• Planned BPA during the fixed duration part of the double-blind period
• Significant obstructive and restrictive lung disease.
• Acute or chronic conditions (other than dyspnea) that limit the ability to comply with study requirements, in particular with 6MWT (eg, intermittent claudication).
• Symptomatic coronary artery disease requiring an intervention within 3 months prior to or during Screening or anticipated during the fixed duration part of the study.
• Decompensated cardiac failure if not under close supervision.
• Known and documented life-threatening cardiac arrhythmias.
• Acute myocardial infarction within 6 months prior to, or during
Screening.
• Cerebrovascular events (including transient ischemic attack) within 3 months prior to, or during Screening.
• Known or suspicion of pulmonary veno-occlusive disease (PVOD).
• Administration of ERAs, intravenous prostacyclins / prostacyclin
analogs, or investigational treatment within 90 days prior to Randomization.
• Change in dose or initiation of PDE-5 inhibitors, oral inhaled or SC
prostacyclins / prostacyclin analogues, prostacyclin receptor agonists
(or riociguat, within 90 days prior to Randomization, or anticipated
during the fixed duration part of the DB period.
• Hypotension, ie, systolic blood pressure (SBP) <90 mmHg or diastolic blood pressure (DBP) <50 mmHg at Screening.
• Severe renal dysfunction with an estimated Glomerular Filtration Rate <30 mL/min/1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration formula at Screening.
• Known moderate to severe hepatic impairment, defined as Child-Pugh Class B or C, based on records that confirm documented medical history.
• Serum aspartate aminotransferase (AST) and/or alanine
aminotransferase (ALT) ≥1.5 the upper limit of normal (ULN) at
Screening.
• Hemoglobin ≤100 g/L (<10 g/dL) at Screening.
• Treatment with strong CYP3A4 inhibitors, (eg, ketoconazole,
itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone,
ritonavir, and saquinavir) or moderate dual CYP3A4/CYP2C9 inhibitors (eg, fluconazole, amiodarone) or coadministration of a combination of moderate CYP3A4 (eg, ciprofloxacin, cyclosporine, diltiazem,erythromycin, verapamil) and moderate CYP2C9 inhibitors (eg, miconazole, piperine), within 30 days prior to Randomization.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline to Week 28 in exercise capacity (6-minute walk distance [6MWD], as measured by the 6-minute walk test [6MWT]).

E.5.1.1

Timepoint(s) of evaluation of this end point

From baseline to Week 28.

E.5.2

Secondary end point(s)

• Time to first Clinical Event Committee (CEC) confirmed clinical worsening up to EODBT.
• Improvement in WHO FC from baseline to Week 28.
• Change from baseline to Week 28 in
• Pulmonary Arterial Hypertension - Symptoms and Impact (PAH-SYMPACT®)
− Cardiopulmonary symptom domain score
− Cardiovascular symptom domain score
• Euro Quality of life-5-Dimension-5-Level (EQ-5D-5L©) utility score.
• Change from baseline to Week 28 in accelerometer-assessed proportion of time spent in moderate to vigorous physical activity.

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 28 and up to End-of-double-blind-treatment (EODBT).

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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

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

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

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

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

Australia

Canada

China

Colombia

Israel

Japan

Korea, Republic of

Mexico

Russian Federation

Saudi Arabia

Serbia

Singapore

Taiwan

Turkey

Ukraine

United States

Austria

Bulgaria

France

Germany

Hungary

Italy

Lithuania

Poland

Romania

Slovakia

Spain

United Kingdom

Czechia

Argentina

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

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:

150

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

F.4.2.2

In the whole clinical trial

230

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)

The options with the patients will be discussed after the end of OL phase.

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

2020-11-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-10-28

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

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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