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    Summary
    EudraCT Number:2013-001353-28
    Sponsor's Protocol Code Number:PSSc-001
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-07-04
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2013-001353-28
    A.3Full title of the trial
    An Open-Label, Randomized, Phase 2 Study of the Safety and Tolerability of Pirfenidone when Administered to Patients with Systemic Sclerosis-Related Interstitial Lung Disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Open-Label, Randomized, Phase 2 Study of the Safety and Tolerability of Pirfenidone when Administered to Patients with Systemic Sclerosis-Related Interstitial Lung Disease
    A.3.2Name or abbreviated title of the trial where available
    LOTUSS
    A.4.1Sponsor's protocol code numberPSSc-001
    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 SponsorInterMune Inc.
    B.1.3.4CountryUnited States
    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 supportInterMune Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTheorem Clinical Research GmbH
    B.5.2Functional name of contact pointProject Management
    B.5.3 Address:
    B.5.3.1Street AddressKönigsteiner Str. 10
    B.5.3.2Town/ cityBad Soden am Taunus
    B.5.3.3Post code65812
    B.5.3.4CountryGermany
    B.5.4Telephone number+49711-6992624
    B.5.5Fax number+4961965228155
    B.5.6E-mailerika.balazs@theoremclinical.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 Esbriet
    D.2.1.1.2Name of the Marketing Authorisation holderInterMune UK Ltd.
    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.3.4Pharmaceutical form Capsule, hard
    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 INNPIRFENIDONE
    D.3.9.1CAS number 53179-13-8
    D.3.9.4EV Substance CodeSUB09907MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number267
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Systemic Sclerosis-Related Interstitial Lung Disease
    E.1.1.1Medical condition in easily understood language
    Systemic Sclerosis-Related Interstitial Lung Disease
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    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 safety and tolerability of pirfenidone at 2403 mg/d when administered to patients with systemic sclerosis-related interstitial lung disease (SSc-ILD)
    E.2.2Secondary objectives of the trial
    To assess the safety and tolerability of two pirfenidone dose-titration schedules
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Eligible patients are to fulfill the preliminary criteria of the American College of Rheumatology for the classification of SSc (Masi 1980) and have a confirmed diagnosis of SSc-ILD based on pulmonary function testing and radiologic data.
    Patients who meet all of the following criteria are eligible to participate in the study:
    Demographic Characteristics:
    1. Male and female patients, aged 18−70 years (inclusive) on Day 1
    SSc− and SSc-ILD−Related Criteria:
    2. Diagnosis of SSc confirmed by the investigator using the preliminary criteria of the American College of Rheumatology for the classification of systemic sclerosis (Masi 1980, Appendix B)
    a. Duration of diagnosis <7 years (dated from the onset of the first non-Raynaud’s phenomenon manifestation, to Day 1 of the study)
    3. Diagnosis of SSc-ILD based on an HRCT scan (obtained in the 2 years before the date of written informed consent) that demonstrates findings consistent with ILD, as assessed by the investigator
    4. Screening FVC ≥50% of the predicted value, and screening DLCO ≥40% of the predicted value
    5. At study entry, the patient either is not taking SSc-ILD medication or is taking cyclophosphamide or MMF, as described below:
    a. Not on SSc-ILD medication: Has not taken SSc-ILD medication in the 3 months before Day 1, or will complete appropriate washout of SSc-ILD medication by Day 1; for such patients, there must be no plan to start another SSc-ILD medication during the study
    b. Taking cyclophosphamide or MMF: Is on an oral formulation of cyclophosphamide (≤2 mg/kg/d) or MMF (≤1.5 g two times daily [BID]), and the dose has been stable in the 3 months before Day 1; for such patients, there must be no plan to change that SSc-ILD medication or its dose during the study
    Informed Consent and Protocol Adherence:
    6. Able to understand and sign a written informed consent form
    7. Able to understand the importance of adhering to study treatment and the study protocol, and willing to follow all study requirements, including the concomitant medication restrictions, throughout the study
    8. Use of effective contraception: Women of childbearing potential are required to have a negative pregnancy test before treatment and must agree to maintain highly effective contraception by practicing abstinence or by using at least two methods of birth control from the date of consent through the end of the study. If abstinence is not practiced, one of the two methods of birth control must be an oral contraceptive (e.g., oral contraceptive and spermicide).
    E.4Principal exclusion criteria
    1. Clinically significant pulmonary hypertension, based on any of the following criteria:
    a. Receiving treatment for pulmonary hypertension
    b. Or, if available, a previous right heart catheterization that demonstrates mean pulmonary artery pressure at rest of ≥25 mm Hg with concurrent wedge pressure of ≤15 mm Hg and pulmonary vascular resistance of >3 Wood units
    c. Or, Doppler echocardiography in the 6 months before D1 with an estimated systolic pulmonary arterial pressure (Ppa) of >36 mm Hg corresponding to a tricuspid regurgitant jet velocity of >2.8 m/sec
    2. Evidence of right atrial or ventricular enlargement or significant left ventricular dysfunction
    3. Known underlying liver disease (e.g., hepatitis or cirrhosis)
    4. Clinical evidence of significant aspiration or uncontrolled gastroesophageal reflux (UCLA SCTC GIT 2.0 reflux score >1.00), as assessed by the investigator
    5. Known achalasia, esophageal stricture, or esophageal dysfunction sufficient to limit the ability to swallow oral medication
    6. Tobacco smoking within 3 months of screening or unwillingness to avoid smoking throughout the study
    7. History of a clinically significant environmental exposure that is known to cause PF including, but not limited to, drugs (e.g., amiodarone), asbestos, beryllium, radiation, or domestic birds or other factors associated with hypersensitivity pneumonitis
    8. History of clinically significant asthma as an adult or clinically significant chronic obstructive pulmonary disease, as assessed by the investigator
    9. Clinical evidence of active infection including, but not limited to, bronchitis, pneumonia, sinusitis, or UTI.
    10. Features supporting diagnosis of another connective-tissue disorder (e.g., RA or SLE) or another pulmonary disorder (e.g., emphysema, asthma, cancer)
    11. Expected to have study participation interrupted for a foreseeable medical or surgical event (e.g., organ, stem cell, or bone marrow transplant).
    12. Any clinical evidence of a malignancy that is likely to result in significant disability or likely to require significant medical or surgical intervention within the next 6 months (relative to D1). Excluded: minor surgical procedures for localized cancer (basal cell carcinoma).
    13. Any condition (other than SSc-ILD) likely to result in the death of the patient within 12 months, as assessed by the investigator
    14. History of unstable or deteriorating cardiac or pulmonary disease (other than SSc-ILD) within the previous 6 months (relative to D1) including, but not limited to unstable angina pectoris, myocardial infarction, congestive heart failure requiring hospitalization, uncontrolled clinically significant arrhythmia, pulmonary hypertension (see Exclusion Criterion 1)
    15. Any condition that, as assessed by the investigator, might be significantly exacerbated by the known side effects associated with pirfenidone
    16. Known or suspected peptic ulcer
    17. Pregnancy or lactation: Positive pregnancy test; currently lactating; or for women of childbearing potential, an unwillingness to maintain highly effective contraception, as described in Inclusion Criterion 8
    18. History of alcohol or substance abuse in the previous 2 years (relative to D1)
    19. Family or personal history of long QT syndrome
    20. Any of the following liver test criteria above the specified limit:
    a. Total bilirubin above ULN, except in patients with predominantly unconjugated hyperbilirubinemia (Gilbert’s syndrome)
    b. AST or ALT >2 × ULN
    c. Alkaline phosphatase >2 × ULN
    d. Creatinine clearance <40 mL/min, calculated using the Cockcroft-Gault formula
    21. Any prior use of pirfenidone
    22. Suspected intolerance, allergy, or hypersensitivity to pirfenidone or any of its excipients
    23. Use of any investigational drug in the 28 days before screening (an investigational drug is defined as any drug that has not been approved for marketing for any indication in the country of the participating site)
    24. Ongoing use or expected use of any of the following therapies:
    a. Investigational therapy
    b. Strong inhibitors of CYP1A2
    c. Moderate inhibitors of CYP1A2 (ciprofloxacin allowed only at doses ≤500 mg BID)
    d. Moderate inducers of CYP1A2
    e. Methotrexate
    f. Cyclosporine
    g. Azathioprine
    h. Rapamycin
    i. Oral corticosteroids at a dose >10 mg/d prednisone equivalent
    j. d-penicillamine
    k. Minocycline
    l. r-relaxin
    m. Interferon-γ
    n. Endothelin-1 receptor antagonists
    o. Phosphodiesterase inhibitors for the treatment of SSc-ILD (e.g., sildenafil or tadalafil), unless used for other indications
    p. TNF-α neutralizing drugs or other biologics used to treat connective-tissue disorders
    q. Treatment with any UV spectrum-containing light, including lasers, and recreational use of any UV spectrum-containing light (e.g., tanning bed)
    Exception: Therapeutic use of non-UV lasers (e.g., IR spectrum lasers)
    25. Unsuitable for enrollment or unlikely to comply with study requirements, as assessed by the investigator
    E.5 End points
    E.5.1Primary end point(s)
    - Evaluation of AEs and SAEs
    - Study treatment discontinuations
    - Treatment-emergent changes in clinical laboratory measures
    - Treatment emergent changes in ECGs
    - Patient responses on the UCLA SCTC GIT 2.0 questionnaire
    - Spirometry
    - DLCO
    - Disease status scales
    E.5.1.1Timepoint(s) of evaluation of this end point
    - AE and SAE monitoring through directed medical history: D-21 to 1, D1, D7, D14, D28, D42, D56, D70, D84, D98, D112 and 28-35 d post dosing
    - Study treatment discontinuations: D7, D14, D28, D42, D56, D70, D84, D98, D112
    - Clinical lab measures (hematology, serum chemistry): D-21 to 1, D1, D14, D28, D56, D84, D112
    - 12-lead ECG: D-21 to 1, D1, D14, D56, D112
    - UCLA SCTC GIT 2.0: D-21 to 1, D1, D28, D56, D84, D112
    - Spirometry: D-21 to 1, D112
    - DLCO: D-21 to 1, D112
    - Disease status scales: D1, D112
    E.5.2Secondary end point(s)
    - Dose modifications and associated AE and SAEs
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Dose modifications: D7, D14, D28, D42, D56, D70, D84, D98, D112
    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 No
    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) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Two dose titration schedules in parallel groups
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    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 concerned2
    E.8.5The trial involves multiple Member States No
    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
    Canada
    United States
    E.8.7Trial has a data monitoring committee No
    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 years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months0
    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.1.1.1In 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: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 9
    F.4.2.2In the whole clinical trial 50
    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)
    None
    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 Decision2013-10-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-07-17
    P. End of Trial
    P.End of Trial StatusCompleted
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