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    Summary
    EudraCT Number:2016-002157-38
    Sponsor's Protocol Code Number:57911
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-07-19
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2016-002157-38
    A.3Full title of the trial
    Treatment of congenital vascular malformations using
    Sirolimus: improving quality of Life
    Behandeling van congenitale vasculaire malformaties met Sirolimus: een studie om de kwaliteit van leven te verbeteren
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of congenital vascular malformations with Sirolimus
    Behandeling van vasculaire vaatmalformaties met Sirolimus
    A.4.1Sponsor's protocol code number57911
    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 SponsorRadboud University Medical Center
    B.1.3.4CountryNetherlands
    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 supportZonMw
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportPfizer
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHECOVAN
    B.5.2Functional name of contact pointwerkgroep@hecovan.nl
    B.5.3 Address:
    B.5.3.1Street AddressGeert Grooteplein
    B.5.3.2Town/ cityNijmegen
    B.5.3.3Post code6500 Hb
    B.5.3.4CountryNetherlands
    B.5.6E-mailwerkgroep@hecovan.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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 Sirolimus or Rapamycin
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer
    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.3.1Product nameSirolimus
    D.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation Yes
    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 INNSIROLIMUS
    D.3.9.1CAS number 53123-88-9
    D.3.9.4EV Substance CodeSUB10537MIG
    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
    congenital vascular malformation : Vascular malformations
    can involve lymphatic vessels, capillaries, veins and arteries or even combinations. These vascular
    malformations are present at birth and grow with the child.
    E.1.1.1Medical condition in easily understood language
    congenital vascular malformation that cannot sufficiently be treated with standard methods like pain medication, surgery or embolisation
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10047091
    E.1.2Term Vascular malformations and acquired anomalies
    E.1.2System Organ Class 100000005125
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10047090
    E.1.2Term Vascular malformation peripheral
    E.1.2System Organ Class 100000158692
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10070181
    E.1.2Term Gastrointestinal vascular malformation
    E.1.2System Organ Class 10017947 - Gastrointestinal disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10074979
    E.1.2Term Vascular malformation
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic 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 investigate whether Sirolimus results in a significant and clinically relevant reduction of pain and an
    improved quality of life in patients with untreatable vascular malformations.
    E.2.2Secondary objectives of the trial
    What length of therapy is required to have and maintain adequate pain reduction?
    Will response to Sirolimus prolong after stop treatment or will there be a rebound?
    Will Sirolimus only have effect on pain reduction or will Sirolimus also inhibit growth/progression of the
    vascular malformation or even lead to reduction of the size of the vascular malformation?
    Which long term consequences can be observed after treatment with Sirolimus e.g. in children?
    Are there genetic factors in the vascular malformation that can predict outcome of treatment with Sirolimus?
    Will Sirolimus lead to a more cost-effective treatment for this patient group?
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Diagnosis of Congenital venous malformation, or lymphatic malformation or combined.
    • Age between 1-60 years.
    • Patients (or legal guardians for children) have to be able to sign the informed consent
    • Patients are either refractory to standard care such as medical treatment (low molecular weight heparines, pain medication etc.), surgical resection and/or sclerotherapy/embolization (ineffective or accompanied by major complications) or there is no possibility for surgical intervention anymore. Only patients that have a normal clinical screening (no signs for infection, normal bone marrow function, normal liver and kidney function, normal glucose metabolism etc.) can be included.
    • Patients included have no cardiac impairment
    • Patients have no gastrointestinal impairment as Sirolimus is absorbed gastro-intestinal and normal function is needed
    • No other underlying medical disorder like Down syndrome or other syndromes
    • Women of reproductive age have to be informed that contraceptive methods are mandatory during the study time, pregnant women are excluded
    • Karnofsky score > 50
    E.4Principal exclusion criteria
    • No written informed consent
    • Known hypersensitivity to drugs or metabolites from similar classes as study
    treatment.
    • Known hypersensitivity to drugs or metabolites from similar classes as study
    treatment.
    • Patient has other concurrent severe and /or uncontrolled medical condition that would, in the investigator’s judgment, contraindicated 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.)
    • Recent history of primary malignancy ≤ 5 years
    • Impaired cardiac function or clinically significant cardiac diseases
    • Immunocompromised patients, including known seropositivity for HIV
    • Patient with any other concurrent severe and /or uncontrolled medical condition that
    would,in the investigator’s judgment, contraindicated participation in the clinical
    study.
    • Pregnant or lactating women
    • Karnofsky score < 50
    E.5 End points
    E.5.1Primary end point(s)
    Endpoints will be evaluated after a time period of six months treatment with Sirolimus:

    Evaluation of Pain
    Quality of Life
    MRI of the vascular malformation
    E.5.1.1Timepoint(s) of evaluation of this end point
    Evaluation will be performed at time point zero:
    pain evaluation
    MRI of the vascular malformation
    Quality of life assesment

    And will subsequently re-evaluated after the treatment period of six months with sirolimus
    E.5.2Secondary end point(s)

    Will Sirolimus also inhibit growth/progression of the vascular malformation or even lead to reduction of the size of the vascular malformation?

    Based on the case reports described in literature, there is a good chance that Sirolimus leads to regression of the vascular malformation. Although this is not the primary objective of the present study, we would like to gain more insight in the percentage of patients this effect can be seen. For this, MRI of the vascular malformation will be made at the beginning of the study and after six months of treatment with Sirolimus. An experienced radiologist will evaluate the evolution of the volume of the malformation


    Are there genetic factors in the vascular malformation that can predict outcome of treatment with Sirolimus?

    Further insight in genotype-phenotype-correlation for venous and/or lymphatic malformations might offer the possibility for better, personalized treatment. It is the question whether Sirolimus will have a positive effect in those patients were no mutation could be found in one of the known genes (PIK3CA/ GNAQ/ AKT-1/ RASA / PTEN/ TIE-2/ Glomulin) involved in vascular malformations. Depending on the results of the present study, we will investigate whether this can be used for further individualization of treatment.

    Adverse events: short and long term consequences of treatment with Sirolimus

    All adverse events occurring will be entered in the Castor Database and scored using the CTCAE criteria version four. Subsequently, at the end of the study all data will be analyzed in SPSS using Chi-square analyses.

    Will the administration of Sirolimus lead to a more cost-effective treatment

    One of the secondary objectives is to evaluate whether the administration of Sirolimus indeed leads to a more cost effective treatment for patients with venous and/or lymphatic malformation. For this reason a cost-effectiveness analysis will be performed from a societal perspective and in accordance with the Dutch guidelines for pharmaco-economic research. This analysis will be performed at te end of the study period of six months
    E.5.2.1Timepoint(s) of evaluation of this end point
    During the fourth year of the study
    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.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 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.8.3 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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: 25
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 3
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 10
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 12
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 48
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    In this trial also children suffering from a severe form of congenital vascular malformation will be included. These children suffer all day of pain and are not capable of having a normal life e.g. going to school, sports and playing with others.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state75
    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)
    We as professionals will submit a reimbursement dossier to the Care Institute at the end of the study for the drug based on the new research. Zorginstituut Nederland has the ability to review an unregistered indication, and may draw a positive stance if warranted by the data . Finally, the college ter beoordeling Geneesmiddelen can also decided that Sirolimus will be registered for a new indication if the data of the present study support this.
    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 Decision2017-09-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-09-23
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