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    Summary
    EudraCT Number:2015-001617-27
    Sponsor's Protocol Code Number:IVA_01_337_HSSC_15_001
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-08-28
    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 ConcernedGermany - BfArM
    A.2EudraCT number2015-001617-27
    A.3Full title of the trial
    A randomized, double-blind, placebo-controlled, multicentre proof-of-concept trial of IVA337 in the treatment of diffuse cutaneous systemic sclerosis
    Eine randomisierte, doppelblinde, placebokontrollierte, multizentrische Proof-of-Concept-Studie mit IVA337 zur Behandlung von diffuser kutaner systemischer Sklerose
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to investigate the efficacy and safety of a new compound for the treatment of diffuse systemic sclerosis, called IVA337.Patients in the trial will be randomly allocated to either the new treatment or a placebo and will be unaware of which treatment they are receiving.
    A.3.2Name or abbreviated title of the trial where available
    IVA337 SSC POC
    A.4.1Sponsor's protocol code numberIVA_01_337_HSSC_15_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 SponsorInventiva SA
    B.1.3.4CountryFrance
    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 supportInventiva SA
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationInventiva
    B.5.2Functional name of contact pointmanager
    B.5.3 Address:
    B.5.3.1Street Address50 rue de Dijon
    B.5.3.2Town/ cityDaix
    B.5.3.3Post code21121
    B.5.3.4CountryFrance
    B.5.4Telephone number33625727211
    B.5.5Fax number33380447561
    B.5.6E-mailsandrine.zourbas@inventivapharma.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 Yes
    D.2.5.1Orphan drug designation numberEMA/OD/129/14
    D.3 Description of the IMP
    D.3.1Product nameIVA337
    D.3.2Product code IVA337
    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 INNLANIFIBRANOR
    D.3.9.1CAS number 927961-18-0
    D.3.9.2Current sponsor codeIVA337
    D.3.9.3Other descriptive name1-(6-BENZOTHIAZOLYLSULFONYL)-5-CHLORO-1H-INDOLE-2-BUTANOIC ACID
    D.3.9.4EV Substance CodeSUB176833
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(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 placeboCapsule, hard
    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
    Systemic sclerosis (scleroderma) (SSc) is a chronic connective tissue disorder of unknown aetiology characterized by widespread microvascular damage and excessive deposition of collagen in the skin and internal organs.
    E.1.1.1Medical condition in easily understood language
    Systemic sclerosis is caused by a build up of fibrous and collagen deposits in the skin and internal organs leading to damage to internal organs.
    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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10012941
    E.1.2Term Diffuse scleroderma
    E.1.2System Organ Class 100000004859
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10074034
    E.1.2Term Generalised scleroderma
    E.1.2System Organ Class 100000004859
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to evaluate in patients suffering from diffuse cutaneous SSc (DcSSc) the effect of 800mg and 1200mg IVA337 daily on the skin compared to placebo. The modified Rodnan Skin Score (MRSS) will be used to determine the changes in skin.
    E.2.2Secondary objectives of the trial
    Secondary objectives include additional efficacy evaluations (details in the protocol), assessment of adverse events (AEs), and determination of population PK parameters of IVA337 in patients.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Systemic sclerosis according to ACR/EULAR 2013 criteria
    •Diffuse cutaneous SSc subset (LeRoy’s criteria)
    •Diagnosis within the past 3 years as defined by the first non-Raynaud’s symptom
    •MRSS between 10 and 25
    • Aged between 18 and 75 years
    • Informed consent documented by signature
    • Patients on stable treatment (for >3 months) with prednisone ≤ 10 mg, methotrexate≤ 20 mg/w, azathioprine ≤ 150 mg/d, mycophenolate
    mofetil ≤ 2g/d, or leflunomide ≤ 20 mg/d may be included in the study;
    the therapy must be maintained as background therapy
    E.4Principal exclusion criteria
    • Cyclophosphamide during the past 3 months
    • Requirement of IV prostanoids for pulmonary hypertension in the last 3 months
    • Renal insufficiency defined by a creatinine clearance of less than 30 ml/min (CKD-EPI or MDRD formula) and/or past/current renal crisis
    • Hepatic impairment i.e. primary biliary cirrhosis and unexplained persistent liver function abnormality,
    • Gallbladder disease (Cholelithiasis is not an exclusion criterion)
    • Diabetic ketoacidosis
    • Severe cardiac (LVEF <45%) and/or pulmonary disease (FVC < 50% or pulmonary hypertension proven by right heart catheterisation)
    • History of heart failure, symptomatic coronary artery disease, significant ventricular tachyarrhythmia, stent placement, coronary artery bypass surgery, and/or myocardial infarction.
    • Recipient of solid organ transplant
    • Gastrointestinal involvement preventing oral administration of study drug
    • Chronic infections, positive serology for infection with hepatitis B or C.
    • Pregnancy, Lactation. Woman of childbearing potential unwilling to use a medically acceptable form of birth control. Such methods include:
    - combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
    - progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
    - intrauterine device (IUD)
    - intrauterine hormone-releasing system ( IUS)
    - bilateral tubal occlusion
    - vasectomised partner
    • History of malignancy within the last 5 years, except for resected basal
    or squamous cell carcinoma of the skin, treated cervical dysplasia, or
    treated in situ cervical cancer
    • A recent history of alcohol or drug abuse, non-compliance with other medical therapies
    • Participation in a clinical study involving another investigational drug
    or device within the past 4 weeks or during the studyg
    • Laboratory parameters at the pre-treatment visit showing any of the following abnormal results: transaminases > 2x the upper limit of normal (ULN) and/or bilirubin > 2x ULN; neutrophil count < 1,500/mm3; platelet count < 100,000/mm3; haemoglobin < 9 g/dL
    • Contraindications to the class of drugs under study (PPAR agonists), e.g. known hypersensitivity or allergy to class of drugs or the investigational product (see IB 2015)
    • Any condition or treatment, which in the opinion of the investigator,
    places the subject at unacceptable risk as a patient in the trial
    • Co-therapy with biologics. Wash-out period: Any anti-TNF agent in the last 3-months: adalimumab, certolizumab, etanercept, golimumab, infliximab, abatacept and tocilizumab in the last 3 months; rituximab in the last 6 months
    • Any other significant heart disease or any clinically significant ECG abnormality reported by central ECG reading
    E.5 End points
    E.5.1Primary end point(s)
    Primary outcome is the mean change of the Modifed Rodnan Skin Score (MRSS) from baseline to week 48
    E.5.1.1Timepoint(s) of evaluation of this end point
    48 weeks
    E.5.2Secondary end point(s)
    EFFICACY
    • MRSS response rates; improvers are defined by a reduction ≥5 points and ≥25 % of MRSS
    • Overall progression of the disease: defined as absence of rescue therapy and absence of severe organ involvement (see definition below)
    • Change in pulmonary function (FVC% predicted and cDLCO% predicted)
    • Changes in patient reported outcomes (SHAQ, UCLA SCTC GIT, PROMIS29, SF36)
    • Digital ulcer net burden (defined as total number of ulcers at a certain time point minus number of ulcers at baseline) and proportion of patients who do not develop new ulcers
    • Cochin Hand Function Scale
    • Physician and patient global assessments of disease activity over the past week (VAS)
    • Change in the Combined Response Index for Systemic Sclerosis (CRISS), consisting of five variables: MRSS, FVC % predicted, physician and patient global assessments, and HAQ-DI score (from SHAQ patient reported outcome)
    • Need for escape therapy (% patients)
    • Severe organ involvement (% patients) defined by
    • new renal crisis OR
    • new or worsened clinically symptomatic and significant heart disease, considered secondary to DcSSc OR
    • Relative decline in FVC % predicted by ≥ 10% or relative decline in FVC % predicted between 5 to < 10% with associated relative decline in DLCO % predicted by ≥ 15%, provided that the decline in FVC results in FVC <75% of predicted OR
    • New or worsening of gastrointestinal disease requiring hospitalization or new requirement for parenteral nutrition OR
    • Critical digital ischemia of the extremities promoting the necrosis or
    gangrene OR
    • New development of pulmonary hypertension associated with
    pulmonary fibrosis – defined by a mean pulmonary arterial pressure of
    25 mmHg or more at right heart catheterization
    •
    •
    SAFETY
    • Frequency and type of AEs
    • Lab tests: mean change and frequency of values outside the normal range
    OTHER
    • Changes in Raynaud phenomenon (Raynaud’s condition score)
    • Mean changes in activity biomarkers
    • Population pharmacokinetics
    • Follow-up: There is a follow-up visit to evaluate any changes that might occur within 4 weeks after completion of the treatment. The performed assessments listed in the Schedule of Study Procedures refer to safety.
    • Evaluate the changes of SSc activity index
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the study at weeks 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52.
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biomarkers study
    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 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.8.2.4Number of treatment arms in the trial3
    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 concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA70
    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
    Switzerland
    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
    last visit of last subject
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months9
    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: 135
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 35
    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 state42
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 164
    F.4.2.2In the whole clinical trial 170
    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
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation EUSTAR
    G.4.3.4Network Country France
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-10-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-09-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-10-12
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