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    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2018-004887-74
    A.3Full 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.3.1Title 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.4.1Sponsor's protocol code numberAC-065D301
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorActelion Pharmaceuticals Ltd
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportActelion Pharmaceuticals Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationActelion Pharmaceuticals Ltd
    B.5.2Functional name of contact pointClinical Trial Disclosure Desk
    B.5.3 Address:
    B.5.3.1Street AddressGewerbestrasse 16
    B.5.3.2Town/ cityAllschwil
    B.5.3.3Post code4123
    B.5.3.4CountrySwitzerland
    B.5.6E-mailclinical-trials-disclosure@its.jnj.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Uptravi
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag International NV
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSelexipag
    D.3.2Product code ACT-293987 / JNJ-67896049
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSELEXIPAG
    D.3.9.2Current sponsor codeACT-293987 / JNJ-67896049
    D.3.9.3Other descriptive nameSELEXIPAG
    D.3.9.4EV Substance CodeSUB130805
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    sarcoidosis-associated pulmonary hypertension (SAPH)
    E.1.1.1Medical condition in easily understood language
    Elevated pressure in lung vessels due to sarcoidosis (i.e. sarcoidosis-associated pulmonary hypertension [SAPH])
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10037400
    E.1.2Term Pulmonary hypertension
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary 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.2.3Trial contains a sub-study Yes
    E.2.3.1Full 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.3Principal 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.4Principal 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.5.1Primary end point(s)
    • PVR at peak concentration at Week 20 expressed as percent of the baseline value.
    E.5.1.1Timepoint(s) of evaluation of this end point
    2 to 5 hours post-dose at week 20
    E.5.2Secondary 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.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    group-sequential; double-blind period followed by open-label period.
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA60
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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.8.7Trial 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.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days18
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days18
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 130
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In 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
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-08-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-10
    P. End of Trial
    P.End of Trial StatusOngoing
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