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    EudraCT Number:2019-003573-26
    Sponsor's Protocol Code Number:TRAMAV02092019
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2019-12-18
    Trial results
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2019-003573-26
    A.3Full title of the trial
    Monocentric pilot trial evaluating efficacy of Trametinib in Arteriovenous Malformations that are refractory to standard treatments or for which standard treatment are contra-indicated
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluating the safety and efficacy of Trametinib in Arterio-Venous Malformations that are refractory to standard care
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberTRAMAV02092019
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCliniques universitaires Saint-Luc
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCTC
    B.5.2Functional name of contact pointGuichet académique
    B.5.3 Address:
    B.5.3.1Street AddressAvenue hippocrate, 10
    B.5.3.2Town/ cityBrussels
    B.5.3.3Post code1200
    B.5.4Telephone number+3227648540
    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. name Mekinist
    D. of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    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 nameMekinist
    D.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Arteriovenous Malformations that are refractory to standard treatments or for which standard treatment are contra-indicated
    E.1.1.1Medical condition in easily understood language
    Arteriovenous Malformations
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The aim of this clinical study is
    1) to confirm the security of trametinib and long-term tolerability in patients with Arteriovenous Malformations (AVM)
    2) to evaluate the efficacy of trametinib on signs and symptoms caused by AVMs that are refractory to standard care
     whether trametinib treatment can alleviate signs and symptoms caused by AVM
     whether trametinib could reduce volume of the malformation (on MRI) on a long-term follow-up
     whether patients will see their quality of life improved.

    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    In order to better delineate the efficacy of this drug, it could be helpful to know the causative gene responsible for each patient involved in the study. This necessitates a small biopsy of the affected tissue, as the mutation will only be in the tissue. This biopsy is not mandatory as biopsy of AVM is sometimes difficult to perform and could be associated with complications. However, if easily accessible and not damaging for the patient, biopsy will be proposed to adult patients. The biopsy will be put in liquid nitrogen or RNA later solution and stored at -80° and in a FFPE block (if available quantity) at room temperature respectively for the duration of the study (i.e. for 7 years). The samples will be stored in the laboratory of Human Molecular Genetics of Prof Miikka Vikkula, de Duve Institute, Catholic university of Louvain, Brussels 1200, Belgium. An additional informed consent will be signed.
    E.3Principal inclusion criteria
    1. Patients with complex and symptomatic fast-flow vascular malformations that are refractory to standard care such as medical treatment, surgical resection and/or embolization (ineffective or accompanied by major complications) or for wich standard care is contra-indicated.
    2. Patients must have adequate bone marrow function: hemoglobine> 10,0 g/dl, neutrophils >1.500/mm³ and platelets > 100.000/mm³.
    3. Patients must have the following laboratory values:
    o Total serum bilirubin ≤ 1.5 x ULN (or totally bilirubin ≤3 x ULN with direct bilirubin ≤ 1.5 x ULN in patients with well documented Gilbert Syndrome)
    o Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (or < 5.0 x ULN if hepatic metastases are present)
    o Serum creatinine < 1.5 x ULN. If the serum creatinine is ≥ 1.5 x ULN, then a 24-hour Creatinine Clearance must be conducted and the result must be ≥ 60 mL/min.
    4. Karnofsky score > 50
    5. Negative urine pregnancy test in females with a childbearing potential.
    6. Sexually active female patients (and female partners of male patients) must use adequate contraceptive measures while on study and for up to 8 weeks after ending treatment.
    E.4Principal exclusion criteria
    1. As AVM can result in impaired cardiac function, congestive heart failure is allowed if stabilized. New York Heart Association functional classification Grade 3-4 congestive heart failure should be excluded from this study, but remains at the discretion of the investigator as trametinib could indirectly improve cardiac function by controlling AVM. Other significant cardiac diseases, including unstable angina pectoris, ventricular arrhythmia, valvular disease with documented compromise in cardiac function, myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function, family history of congenital long or short QT, or known history of QT/QTc prolongation of Torsades de Pointes (TdP) are excluded from this trial.
    2. Impairment of Gastro-Intestinal (GI) function or GI disease that may significantly alter the absorption of trametinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea ≥ Grade 2, malabsorption syndrome, or small bowel resection)
    3. Known hypersensitivity to drugs or metabolites from similar classes as study treatment.
    4. Patient has (an)other concurrent severe and /or uncontrolled medical condition(s) that would, in the investigator’s judgement, contraindicate participation in the clinical study (e.g. acute or chronic pancreatitis, liver cirrhosis, active chronic hepatitis, severely impaired lung function with a spirometry ≤ 50% of the normal predicted value and/or O2 saturation ≤ 88% at rest, etc.)
    5. Patient with history of Retinal pigment epithelial detachments or Retinal vein occlusion
    6. Immunocompromised patients, including known seropositivity for HIV
    7. Pregnant or lactating women
    E.5 End points
    E.5.1Primary end point(s)
    All patients will be seen monthly for the first 3 months and then every three months, in order to evaluate the efficacy and safety of trametinib. Doppler ultrasonography and cardiac echography (Ventriculography) will be performed in baseline and at 6, 12 and 24 months; Magnetic Resonance Imaging (MRI) and arteriography will be performed at baseline, 12 and 24 months.
    E.5.1.1Timepoint(s) of evaluation of this end point
    2 years
    E.5.2Secondary end point(s)
    At the end of 2 years, the treatment is interrupted and the patient is followed during 5 years. In case of resurgence of symptoms, trametinib could be restarted.
    E.5.2.1Timepoint(s) of evaluation of this end point
    5 years
    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 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. 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 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 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 No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 No
    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
    5 years
    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 months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 10
    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) Yes
    F. of subjects for this age range: 5
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 5
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) No
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state20
    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)
    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 Decision2020-03-12
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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