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    Summary
    EudraCT Number:2010-022710-77
    Sponsor's Protocol Code Number:AC-055C301
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-08-26
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBulgarian Drug Agency
    A.2EudraCT number2010-022710-77
    A.3Full title of the trial
    Prospective, randomized, placebo-controlled, double-blind, multicenter, parallel group study to assess the efficacy, safety and tolerability of macitentan in patients with ischemic digital ulcers associated with systemic sclerosis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical research study with macitentan evaluating its effects on digital ulcers associated with systemic sclerosis (scleroderma)
    A.3.2Name or abbreviated title of the trial where available
    DUAL-1: Digital Ulcers with mAcitentan in systemic scLerosis
    A.4.1Sponsor's protocol code numberAC-055C301
    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 pointGlobal Medical Information
    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-mailmedinfo_ch@actelion.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 No
    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 namemacitentan
    D.3.2Product code macitentan
    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 INNmacitentan
    D.3.9.1CAS number 441798-33-0
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    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.IMP: 2
    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 No
    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 namemacitentan
    D.3.2Product code macitentan
    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 INNmacitentan
    D.3.9.1CAS number 441798-33-0
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    Ischemic digital ulcers associated with systemic sclerosis
    E.1.1.1Medical condition in easily understood language
    Difficult-to-heal open sores on fingers ("Digital Ulcers") associated with a disease that leads to hardening of the skin, blood vessels and internal organs ("Systemic sclerosis")
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level PT
    E.1.2Classification code 10042953
    E.1.2Term Systemic sclerosis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue 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 demonstrate the effect of macitentan on the reduction of the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer (DU) disease.
    E.2.2Secondary objectives of the trial
    _To evaluate the efficacy of macitentan on hand functionality in systemic sclerosis (SSc) patients with active DUs.
    _ To evaluate the safety and tolerability of macitentan in SSc patients with active DUs.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Diagnosis of limited or diffuse SSc according to the classification criteria of the American College of Rheumatology (ACR), including CREST (calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia) syndrome.
    - At least one visible, active ischemic DU at baseline, located on the palmar surface of a finger, at or distal to the proximal interphalangeal joints (PIP) or at the digital tip, and that developed within 8 weeks prior to randomization.
    - History of at least one additional active ischemic DU within 6 months, or at least two within 12 months prior to Screening.
    E.4Principal exclusion criteria
    1. DUs due to condition other than SSc.
    2. Symptomatic pulmonary arterial hypertension (PAH).
    3. Body mass index (BMI: kg/m2) <18.
    4. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal (ULN).
    5. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
    6. Hemoglobin < 75% of the lower limit of the normal range.
    7. Systolic blood pressure < 100 mmHg or diastolic blood pressure < 50 mmHg .
    8. Renal insufficiency (estimated creatinine clearance <30 mL/min, or serum creatinine > 2.5mg/dL).
    9. Severe malabsorption, any severe organ failure (e.g., lung,kidney), or any life-threatening condition.
    10. Conditions that could affect hand function and hand pain, based on investigator discretion.
    11. Females who are pregnant or breastfeeding or plan to do so during the course of this study.
    12. Substance or alcohol abuse or dependence, or tobacco use .
    13. Treatment with PDE5 inhibitors (e.g., sildenafil, tadalafil).
    14. Patients on statins (e.g., atorvastatin, simvastatin), who have received treatment for less than 3 months prior to Screening (Visit 1) or whose treatment has not been stable during this period.
    15. Patients on vasodilatorsand low molecular weight heparin.
    16. Treatment with prostanoids.
    17. Treatment with endothelin receptor antagonists (ERAs).
    18. Systemic antibiotics (oral and i.v.) to treat infected DU(s) .
    19. Use of topical growth factors, hyperbaric oxygen.
    20. Local injection of botulinum toxin in an affected finger within 4 weeks prior to Screening.
    21. Surgical wound debridement within 1 month prior to Screening.
    22. Treatment with cytochrome P450 3A (CYP3A) inducers, such as rifabutin, rifampin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John’s wort, within 4 weeks prior to Screening.
    23. Known hypersensitivity to drugs of the same class as the study drug, or any of the excipients.
    24. Planned treatment, or treatment with another investigational drug within 4 weeks prior to Screening.
    25. Any condition that prevents compliance with the protocol or adherence to therapy, such as inability to speak, read, or understand the local language well enough to complete all study assessments.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint (assessed during Treatment Period 1) :
    Total number of new DUs per patient at planned visits up to Week 16.
    E.5.1.1Timepoint(s) of evaluation of this end point
    End-of-Period 1 (Week 16)
    E.5.2Secondary end point(s)
    Secondary endpoints (assessed during Treatment Period 1)
    - Proportion of patients without a new DU up to Week 16.
    - Change from baseline (Visit 2) to Week 16 in the Cochin Hand Functional Scale (CHFS) overall and individual domain scores.
    - Change from baseline (Visit 2) to Week 16 in the composite of hand components of the disability index of the Scleroderma Health Assessment Questionnaire (SHAQ): grip, hygiene, dressing and grooming.
    - Change from baseline to Week 16 in the total number of DUs observed (baseline DUs and new DUs).
    - Time to onset of each new DU up to Week 16 (time to 1st, 2nd, 3rd, 4th, etc., DU).

    Secondary endpoints (assessed during Treatment Period 2):
    - Proportion of patients without a new DU during Treatment Period 2 [from re-randomization (Visit 6) to EOT (Visit 9)] among patients who received either macitentan 3 or 10 mg and did not develop any new DU during Treatment Period 1.
    - Time from re-randomization (Visit 6) to the occurrence of the first new DU during Treatment Period 2 among patients who received either macitentan 3 or 10 mg and did not develop any new DU during Treatment Period 1.
    - Total number of new DUs per patient during Treatment Period 2 [from re-randomization (Visit 6) to EOT (Visit 9)] among patients who received either macitentan 3 or 10 mg and developed at least one new DU during Treatment Period 1.
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Treatment period 1: 4 visits (week 4, 8, 12 and 16)
    - Treatment period 2: 3 visits (week 20, 24 and 28)
    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) No
    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 No
    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.8.3 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA35
    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
    Australia
    Belarus
    Bulgaria
    Canada
    Chile
    Colombia
    Croatia
    Czech Republic
    Denmark
    Finland
    France
    Germany
    Hungary
    India
    Italy
    Poland
    Russian Federation
    Ukraine
    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
    Last Patient Last Safety Follow-up : 30 days after LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    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: 242
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 43
    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 state32
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 140
    F.4.2.2In the whole clinical trial 285
    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)
    When the results of the AC-055C301 and AC-055C302 studies become available and a statistically significant favorable effect on ischemic DU with macitentan is demonstrated, an open-label study (under a separate protocol) may be offered to patients who complete the study as scheduled.
    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 Decision2011-08-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-11-17
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-11-29
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