Clinical Trials Register

Summary
EudraCT Number:	2018-004887-74
Sponsor's Protocol Code Number:	AC-065D301
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-06-26
Trial 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

Poland - Office for Medicinal Products

A.2

EudraCT number

2018-004887-74

A.3

Full title of the trial

A multicenter, randomized, double-blind, group-sequential, placebo-controlled 52-week period followed by a 104-week, single-arm, open-label period study in participants with sarcoidosis-associated pulmonary hypertension (SAPH) to assess the efficacy and safety of oral selexipag.

A.3.1

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

A study of the effectiveness and safety of selexipag in patients with sarcoidosis-associated pulmonary hypertension.

A.4.1

Sponsor's protocol code number

AC-065D301

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	Actelion Pharmaceuticals Ltd
B.5.2	Functional name of contact point	Clinical Trial Disclosure Desk
B.5.3	Address:
B.5.3.1	Street Address	Gewerbestrasse 16
B.5.3.2	Town/ city	Allschwil
B.5.3.3	Post code	4123
B.5.3.4	Country	Switzerland
B.5.6	E-mail	clinical-trials-disclosure@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 / JNJ-67896049
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 / JNJ-67896049
D.3.9.3	Other descriptive name	SELEXIPAG
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

sarcoidosis-associated pulmonary hypertension (SAPH)

E.1.1.1

Medical condition in easily understood language

Elevated pressure in lung vessels due to sarcoidosis (i.e. sarcoidosis-associated pulmonary hypertension [SAPH])

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10037400
E.1.2	Term	Pulmonary 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 assess the effect of selexipag versus placebo on pulmonary vascular resistance (PVR) in participants with sarcoidosis-associated pulmonary hypertension (SAPH) at Week 20.

E.2.2

Secondary objectives of the trial

• To evaluate the effect of selexipag versus placebo on time to clinical worsening (TTCW).
• To evaluate the effect of selexipag versus placebo on exercise capacity.
• To evaluate the effect of selexipag versus placebo on WHO FC.
• To evaluate the effect of selexipag versus placebo on death or PH-related hospitalizations.
• To evaluate the effect of selexipag versus placebo on patient-reported outcomes (PROs) assessed by the 12-Item Short Form Health Survey (SF-12), King’s sarcoidosis questionnaire (KSQ), Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT), and Patient Global Assessment of Severity (PGA-S).
• To evaluate the effect of selexipag versus placebo on clinician-reported outcomes (CROs) assessed by the Clinician Global Impression of Severity (CGI-S) and Clinician Global Impression of Change (CGI-C).
• To assess the overall safety of selexipag.

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

A 52-week substudy to assess pulmonary fibrosis using centrally read HRCT. Objective: To explore the effect of selexipag on pulmonary fibrosis in a subset of participants.

A 52-week substudy to assess cardiac function and structure using centrally read cardiac MRI will be conducted at selected sites with appropriate equipment and experience. Objective: To explore the effect of selexipag on right ventricular (RV) function and morphology in a subset of participants.

E.3

Principal inclusion criteria

1. Must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
2. Male or female.
3. 18 (or the legal age of consent in the jurisdiction in which the study is taking place) to 75 years of age, inclusive, at Screening.
4. Confirmed diagnosis of sarcoidosis as per ATS criteria.
5. Sarcoidosis-associated precapillary PH, confirmed by RHC (at rest) within 90 days prior to randomization:
a. PVR ≥240 dyn*sec/cm5 (≥3.0 Wood units)
b. Mean pulmonary artery pressure (mPAP) ≥25 mmHg
c. Pulmonary artery wedge pressure (PAWP) ≤15 mm Hg, or if not available or unreliable, a left ventricular end diastolic pressure (LVEDP) ≤15 mmHg.
6. PH severity according to modified WHO FC II–IV at Screening and randomization; participants of WHO FC IV must be in a stable condition and able to perform a 6MWT.
7. No treatment or stable treatment of PH (ie, riociguat, PDE5i, ERA) during at least 90 days prior to randomization and the RHC qualifying for enrollment, (ie, no introduction of new therapies or dose change).
8. Stable sarcoidosis treatment regimen, ie, no new specific anti-inflammatory treatment for sarcoidosis for at least 90 days, and stable dose(s) for at least 30 days prior to randomization and the RHC qualifying for enrollment.
9. 6MWD between 50 and 450m both at Screening and at time of randomization.
10. Forced vital capacity (FVC) >50% and FEV1 >30% of predicted at Screening.
11. FEV1/FVC ≥60%, or if FEV1/FVC <60% then FEV1 must be ≥65% of predicted at Screening.
12. For patients enrolling in the HRCT substudy only: clinical and/or radiological suspicion of pulmonary fibrosis.
13. For patients enrolled or planned to be enrolled in a cardio-pulmonary rehabilitation program based on exercise training, one of the following must apply:
• In the maintenance phase of the program at the time of randomization with no plans to stop the program until Week 26, or
• Start of the cardio-pulmonary rehabilitation program based on exercise training is planned after Week 26.
14. A woman must be (as defined in Appendix 5)
a. Not of childbearing potential
b. Of childbearing potential and
o Have a negative highly sensitive serum (β-human chorionic gonadotropin [β-hCG]) at Screening and a negative urine pregnancy test at randomization.
o Agree to undertake monthly urine pregnancy tests during the study and up to at least 30 days after study intervention discontinuation.
o Practicing an acceptable method of contraception and agree to remain on an acceptable method while receiving study intervention and until 30 days after last dose of study intervention. Examples of acceptable methods of contraception are located in Appendix 5.
15. A woman using oral contraceptives must have been using this method for at least 1 month prior to randomization.

E.4

Principal exclusion criteria

1. PH due to left heart disease (PAWP >15 mmHg).
2. PH due to compression of pulmonary arteries and/or pulmonary veins.
3. History of left heart failure (LHF) as assessed by the investigator including cardiomyopathies, cardiac sarcoidosis, with a left ventricular ejection fraction (LVEF) <40%.
4. Severe coronary heart disease (CHD) or unstable angina as assessed by the investigator.
5. Myocardial infarction within the last 6 months prior to or during Screening.
6. Decompensated cardiac failure if not under close supervision.
7. Arrhythmias assessed as severe by the investigator.
8. Implantable cardioverter defibrillator (ICD) for secondary prevention.
9. Cerebrovascular events (eg, transient ischemic attack, stroke) within the last 90 days prior to or during Screening.
10. Congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to PH.
11. Overt features of pulmonary veno-occlusive disease (PVOD).
12. Significant emphysema as assessed by the investigator.
13. Known and documented severe hepatic impairment (Child-Pugh C).
14. Severe renal failure (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2 or serum creatinine >2.5 mg/dL) based on central laboratory results from the Screening blood sample.
15. Treatment with prostacyclin, prostacyclin analogues or IP receptor agonists (ie, selexipag) during 90 days prior to randomization and/or prior to the RHC qualifying for enrollment, except those given at vasodilator testing during RHC.
16. Included on a lung transplant list or planned to be included until Visit 5 / Week 26.
17. Known or suspected uncontrolled thyroid disease as per investigator judgment.
18. Treatment with moderate inducers of CYP2C8, eg rifampicin or strong inhibitors of CYP2C8, eg, gemfibrozil at or within 14 days prior to randomization.
19. Change in dose or initiation of new diuretics and/or calcium channel blockers within 1 week prior to RHC qualifying for enrollment.
20. SBP <90 mmHg at Screening or at randomization.
21. Known allergies, hypersensitivity, or intolerance to selexipag or its excipients (refer to Investigator’s Brochure).
22. Planned or current treatment with another investigational treatment up to 90 days prior to randomization.
23. Received an investigational intervention or used an invasive investigational medical device within 90 days prior to randomization.
24. Any condition for which, in the opinion of the investigator, participation would not be in the best interests of the participant (eg, compromise well-being), or that could prevent, limit, or confound the protocol-specified assessments.
25. Any acute or chronic impairment that may influence the ability to comply with study requirements such as to perform RHC, a reliable and reproducible 6MWT (eg, use of walking aids (cane, walker, etc.), or lung function tests.
26. Employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator.
27. For patients enrolling in the HRCT substudy only: any condition for which, in the opinion of the investigator, participation would not be in the best interests of the participant (eg, compromise well-being).
28. For patients enrolling in the cardiac MRI substudy only: atrial fibrillation, multiple premature ventricular or atrial contractions, or any other condition that may confound cardiac MRI assessment or for which, in the opinion of the investigator, participation would not be in the best interests of the participant (eg, compromise well-being).

E.5 End points

E.5.1

Primary end point(s)

• PVR at peak concentration at Week 20 expressed as percent of the baseline value.

E.5.1.1

Timepoint(s) of evaluation of this end point

2 to 5 hours post-dose at week 20

E.5.2

Secondary end point(s)

• TTCW (defined according to definition by the CHMPb) up to Week 52 defined as at least one of the following components:
o All-cause death
o Non-planned pulmonary hypertension (PH)-related hospitalization
o Increase in WHO functional class (FC)
o Deterioration by at least 15% from baseline in exercise capacity as measured by the 6-minute walk distance (6MWD);
o Signs or symptoms of right heart failure (RHF) defined as a reported adverse event (AE) with one of the following preferred terms: “pulmonary hypertension”, “right ventricular failure”, “right ventricular dysfunction” and “acute right ventricular failure”.
• Longitudinal trend of 6MWD up to Week 52.
• Proportion of participants with oxygen desaturation post 6-minute walk test (6MWT) up to Week 52 (identified by decrease in oxygen saturation [SpO2] by at least 5% from pre-6MWT).
• Proportion of participants with improvement, worsening and no change from baseline in WHO FC up to Week 52.
• Proportion of participants with all-cause death or PH-related hospitalization up to Week 52.
• Rate of all-cause death or PH-related hospitalization up to Week 52.
• Change from baseline up to Week 52 in SF-12 scores.
• Change from baseline up to Week 52 in KSQ scores.
• Change from baseline up to Week 39 in PAH-SYMPACT scores.
• Change from baseline up to Week 52 in PGA-S scores.
• Change from baseline up to Week 52 in CGI-S scores.
• Change from baseline up to Week 52 in CGI-C scores.
• Intervention-emergent AEs.
• Intervention-emergent prostacyclin-associated AEs.
• Serious adverse events (SAEs) up to End-of-Study (EOS).
• AEs leading to premature discontinuation of study treatment.
• Treatment-emergent AEs of special interest (eg, hypotension, anemia, hyperthyroidism).
• Change in vital signs (systolic and diastolic arterial blood pressure and pulse rate) and body weight from baseline to all assessed timepoints during the study.
• Treatment-emergent marked laboratory abnormalities.
• Change from baseline in supplemental oxygen rate.

E.5.2.1

Timepoint(s) of evaluation of this end point

All timepoints as collected per protocol up to week 52 and EOS will be anaylsed.
AE, SAE, death and hospitalisation will be assessed at scheduled visits.

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)

Yes

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

Yes

E.8.1.7.1

Other trial design description

group-sequential; double-blind period followed by open-label period.

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

Argentina

Belgium

Brazil

Canada

China

Czech Republic

Denmark

France

Germany

Hungary

India

Italy

Mexico

Netherlands

Poland

Portugal

Romania

Russian Federation

Spain

Sweden

Turkey

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

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:

130

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

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

150

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)

After the participant’s study completion, the investigator/delegate will explain what treatment(s) / medical care is necessary and available according to local regulations. If indicated, the sponsor will provide participants who completed the study and did not prematurely discontinue study intervention with selexipag until access to commercial selexipag is possible in this indication in the participant’s country of residence, according to local regulatory requirements.

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

2019-08-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-07-10

P. End of Trial
P.	End of Trial Status	Ongoing

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