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    Summary
    EudraCT Number:2019-003585-40
    Sponsor's Protocol Code Number:NL.TACRO.10.7.19
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-09-30
    Trial 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 number2019-003585-40
    A.3Full title of the trial
    An uncontrolled, open label pilot-study assessing the efficacy in reducing bleeding severity, and the safety of oral tacrolimus in patients with hereditary hemorrhagic telangiectasia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Tacrolimus for bleeding in hereditary hemorrhagic telangiectasia patients
    A.3.2Name or abbreviated title of the trial where available
    Tacrolimus for bleeding in HHT patients
    A.4.1Sponsor's protocol code numberNL.TACRO.10.7.19
    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 SponsorSt. Antonius Hospital
    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.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSt. Antonius Hospital
    B.5.2Functional name of contact pointS. Kroon
    B.5.3 Address:
    B.5.3.1Street AddressKoekoekslaan 1
    B.5.3.2Town/ cityNieuwegein
    B.5.3.3Post code3435CM
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031883201579
    B.5.5Fax number0031883201449
    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 Tacrolimus (Advagraf)
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameTacrolimus (Advagraf)
    D.3.2Product code EMEA/H/C/000712
    D.3.4Pharmaceutical form Capsule
    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.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
    Gastrointestinal bleeding and epistaxis caused by hereditary hemorrhagic telangiectasia. Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant inherited disease characterized by mucocutaneous telangiectasis. Telangiectasis predominantly observed in the nasal mucosa and gut, and are abnormal, thin walled blood vessel that can easily rupture leading to hemorrhage.
    E.1.1.1Medical condition in easily understood language
    A genetic disorder called Hereditary Hemorrhagic Telangiectasia, also known as Rendu-Osler-Weber syndrome
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10038554
    E.1.2Term Rendu-Osler-Weber syndrome
    E.1.2System Organ Class 100000004850
    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 efficacy and safety of oral tacrolimus in reducing bleeding severity in HHT patients with severe epistaxis and/or gastrointestinal bleeding. The primary objective is to measure the hemoglobin level at the beginning and during the trial.
    E.2.2Secondary objectives of the trial
    As secondary outcomes, reduction in the epistaxis severity score (ESS), quality of life, the safety (side-effects, (s)AEs) of the therapy, and difference in monthly epistaxis duration, epistaxis frequency, the use of iron infusions, blood transfusions, mean ferritin will be evaluated after 20 weeks of therapy compared to the parameters at baseline.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1. Oral tacrolimus for epistaxis in hereditary hemorrhagic telangiectasia
    2. Oral tacrolimus for gastrointestinal bleeding in hereditary hemorrhagic telangiectasia
    E.3Principal inclusion criteria
    • Patients with HHT:
    o Definite HHT according to the Curacao criteria (3 positive criteria or more)
    AND/OR
    o Genetically confirmed HHT
    • Suffering from epistaxis at least on average of 4 days per week or documented gastrointestinal teleangiectasis by endoscopy with suspicion of bleeding;
    • In the last six months suffering from anemia, iron deficiency or use iron treatment or blood transfusions;
    • Failure or partial failure of local treatment with systemic treatment indicated by ENT specialist or gastroenterologist;
    • Adult (18 years or older at time of inclusion).
    E.4Principal exclusion criteria
    • Hypersensitivity or allergy for tacrolimus
    • Patients with a severe disease with a life-expectancy <1 year;
    • Women that are pregnant, nursing, have a pregnancy wish in the study period or who use anticonception inadequately;
    • Patients currently receiving chemotherapy;
    • Patients receiving drugs that are contraindicated when using tacrolimus (see chapter 14.1, section G).
    • Patients who do not understand English or Dutch language sufficiently enough;
    • Patients who refuse informed consent.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome of this study is the difference in hemoglobin levels at the baseline compared to that at the end of the trial
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary end point will be evaluated at the baseline and at the end of the trial. The difference will be calculated
    E.5.2Secondary end point(s)
    • Difference in monthly epistaxis severity measured with:
    o Epistaxis severity score (ESS);
    o Monthly number of episodes;
    o Monthly duration;
    o Monthly intensity;
    o VAS score of epistaxis.
    • Difference in biochemical blood values: Hb and ferritin.
    • Differences in required number of blood transfusions and iron infusions.
    • Difference in quality of life with SF-36 and fatigue complaints (MFI-20) between baseline and end of the study.
    E.5.2.1Timepoint(s) of evaluation of this end point
    All the secondary end points will be evaluated at the baseline and at the end of the trial. The only exception is the difference in required number of blood transfusions and iron infusions. We will compare the number of required number of blood transfusions and iron infusions during the trial (20 weeks) and to the same period prior to the trial
    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 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 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 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 months6
    E.8.9.1In the Member State concerned 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: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 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)
    After the trial has ended tacrolimus treatment is stopped and patients are followed up after one and three months by the researcher, and life time by their treating physicians. If the bleeding reoccurs, patients are allowed to restart tacrolimus treatment. The tacrolimus treatment will then be coordinated by the treating pulmonologists of the St. Antonius Hospital, experienced with tacrolimus treatment for HHT.
    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 Decision2019-09-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-17
    P. End of Trial
    P.End of Trial StatusOngoing
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