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    Summary
    EudraCT Number:2008-008652-16
    Sponsor's Protocol Code Number:BR1-129
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2009-10-01
    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 number2008-008652-16
    A.3Full title of the trial
    QUANTITATIVE EVALUATION OF SONOVUE ENHANCED ULTRASONOGRAPHY FOR EARLY IDENTIFICATION OF SUBJECTS WITH HEPATOCELLULAR CARCINOMA REFRACTORY TO SORAFENIB THERAPY : A PHASE II EXPLORATIVE, INTRA-PATIENT COMPARATIVE STUDY VERSUS CONTRAST ENHANCED MDCT/MRI IMAGING
    A.3.2Name or abbreviated title of the trial where available
    BR1-129
    A.4.1Sponsor's protocol code numberBR1-129
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberND
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBRACCO IMAGING
    B.1.3.4CountryItaly
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 SONOVUE
    D.2.1.1.2Name of the Marketing Authorisation holderBRACCO SpA DIV.FARMACEUTICA
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 Powder and solvent for suspension for injection
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSulfur hexafluoride
    D.3.10 Strength
    D.3.10.1Concentration unit µl/ml microlitre(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number8
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Yes
    D.3.11.13.1Other medicinal product typemezzo di contrasto
    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
    HCC epatocellular carcinoma
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level HLT
    E.1.2Classification code 10025577
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess whether perfusion changes in one target HCC lesion assessed quantitatively by CE-US at week 2 and 4 of Sorafenib therapy can predict progression of disease at week 8 assessed by CE-MDCT/MRI, using standard RECIST criteria.
    E.2.2Secondary objectives of the trial
    1.To determine if perfusion changes in one target HCC lesion assessed quantitatively by CE-US at wk 2 and 4 of Sorafenib therapy: a)can predict progression of disease at wk 8 with CE-MDCT/MRI, using Llovet crit. b)correlate with OS c)correlate with TTP using RECIST/Llovet crit. d)can predict progression of the same lesion at wk 8 assessed with CE-MDCT/MRI,using Llovet crit. 5.In responder subj. at wk 8, to determine if perfusion changes in the target HCC lesion assessed quantitatively by CE-US at wk > 8 can identify earlier than CE-MDCT/MRI, HCC progression after wk 8. 6.To assess if progression of the target HCC lesion determined by the investigator based on qualitative evaluation of CE-US findings at wk 2 and 4 of Sorafenib therapy predict progression of disease at wk 8 assessed by CE-MDCT/MRI,using RECIST crit. 7.to compare diagnosis of qualitative evaluation of CE-US vs the best quantitative one for predict 1resistance to sorafenib 8. to assess safety of SonoVue
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Adult (age > or = 18 years) male or female; Providing written informed consent and willing to comply with protocol requirements; Confirmed diagnosis of advanced HCC either based on histology or based on AASDL criteria,as follows: -nodule < or = 1 cm in maximum diameter: histology. -nodule of 1-2 cm in diameter: two imaging procedures (CE-CT and CE-MRI or CE-US) showing coincidental typical vascular pattern for HCC (contrast uptake in the arterial phase and washout in venous or late phases). -nodule >2 cm in maximum diameter: one imaging procedure (CE-CT or CE-MRI or CE-US) showing typical vascular pattern for HCC (contrast uptake in the arterial phase and washout in venous or late phases). Candidate to start sorafenib as monotherapy. At least one liver lesion, measurable according to RECIST criteria1 and evaluable by CE-US defined as: -Acoustic window sufficient for adequate US examination of the liver (all target HCC borders should be correctly visualized by B-mode and lesions adjacent to diaphragmatic border should be avoided). -Not previously treated -Diameter of 2 cm or more -Perfused area &amp;#8805; 50% of the total volume. At least 4 weeks since prior surgery/treatment with resolution of all acute toxic effects.
    E.4Principal exclusion criteria
    Has any clinically unstable cardiac condition prior to SonoVue&amp;#61666; administration such as: -evolving or ongoing myocardial infarction, -a history of acute myocardial infarction or percutaneous coronary interventions (PCI) within the previous 3 months, -worsening of typical angina at rest within the previous 7 days, -significant worsening of cardiac symptoms within the previous 7 days, -recent coronary artery intervention or other factors suggesting clinical instability (e.g., recent deterioration of ECG, laboratory or clinical findings), -cardiac failure Class III/IV in accordance to the New York Heart Association , -severe cardiac rhythm disorders (ventricular tachycardia sustained and not sustained in combination with symptoms, flutter fibrillation, ventricular premature complexes occurring close to the preceding T-wave, multifocal complexes). Has respiratory failure or a known history of pulmonary hypertension. Known allergy to one or more of the ingredients of the investigational product. Known allergy to iodinated contrast agents and MRI contrast agents. Any other contraindication to one of the imaging examinations (US, CT or MRI) e.g. implants, claustrophobia, inadequate medical conditions etc. Any contraindication to sorafenib Has received an investigational compound within 30 days before admission into this study. Has any medical condition or other circumstances which would significantly decrease the chances of obtaining reliable data, achieving study objectives, or completing the study and/or post dose follow-up examinations. Subject clinically unsuitable for the study as per Investigators judgment. Pregnant and lactating women. A pregnancy test (serum &amp;#946;HCG or urine stick) should be carried out within 24 hours prior to the administration of the investigational product to exclude pregnancy in women of child bearing potential.
    E.5 End points
    E.5.1Primary end point(s)
    Perfusion changes will be evaluated by CE-US using a dedicated quantification software (SONOTUMOR) that allows calculation of several functional quantitative parameters including parameters related to blood volume (area under curve, perfusion index, maximum intensity, relative perfused area, perfused area) and parameters related to perfusion dynamics (mean transit time, time to peak, wash-in rate and wash-out rate, rise time).
    The primary quantitative parameter for evaluation of subject outcome based on CE-US cannot be selected a priori as no validated parameter and no validated response criteria are available yet.
    Thus, the predictiveness of the variations (% changes and absolute changes) of each of the parameters calculated by the software will be explored with the intent to select the most suitable one for prediction of subject outcome. Thus, the best parameter(s), its relevant threshold value(s), and the best time for identification of non responding subjects will be identified a posteriori.For the purpose of the analysis, overall tumor response at week 8 of therapy based on RECIST criteria and RECIST modified according to Llovet et al. will be grouped in two categories, as follows:
    Non Responders = progressive disease [PD];
    Responders = complete response [CR] + partial response [PR] + stable disease [SD]
    Primary end-point: to correlate the variations (% change and absolute change vs. baseline) of functional quantitative parameters assessed by CE-US in one target HCC at week 2 and 4 of sorafenib therapy in comparison to baseline vs. progression of disease as assessed by CE-MDCT/MRI at week 8 using RECIST criteria.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    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 No
    E.8.1.2Open No
    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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    CE-US vs CE MDCT/MRI
    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 concerned22
    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 No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    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
    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.1.3Elderly (>=65 years) Yes
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2009-10-01. Yes
    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 state168
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 168
    F.4.2.2In the whole clinical trial 168
    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 Decision2009-10-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-09-15
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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