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    Summary
    EudraCT Number:2019-000608-14
    Sponsor's Protocol Code Number:1.0/170119
    National Competent Authority:Estonia - SAM
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2019-03-14
    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 ConcernedEstonia - SAM
    A.2EudraCT number2019-000608-14
    A.3Full title of the trial
    Prospective validation of individualized Bayesian dose optimization tool DosOpt for Vancomycin treatment in neonates.
    Bayesi indiviidipõhise vankomütsiini doosi optimeerimise tarkvara DosOpt’i prospektiivne valideerimine vastsündinutel
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Vancomycin dosage trial
    Vankomütsiini doseerimise uuring
    A.3.2Name or abbreviated title of the trial where available
    DosOpt
    DosOpt
    A.4.1Sponsor's protocol code number1.0/170119
    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 SponsorTartu University Hospital
    B.1.3.4CountryEstonia
    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 supportTartu University Hospital
    B.4.2CountryEstonia
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation Anaesthesiology and Intensive Care Clinic
    B.5.2Functional name of contact pointPediatric Intensive Care Unit
    B.5.3 Address:
    B.5.3.1Street AddressL.Puusepa 8
    B.5.3.2Town/ cityTartu
    B.5.3.4CountryEstonia
    B.5.6E-mailtuuli.metsvaht@kliinikum.ee
    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 Vancosan 500 mg
    D.2.1.1.2Name of the Marketing Authorisation holderMIP Pharma GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEstonia
    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 solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous 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
    In neonatal population wide inter-and intra-individual variability of pharmacokinetics makes extremely difficult to ensure optimal exposure of vancomycin with standard regimens. On average >50% of baseline drug concentrations are out of target (10-15 mg/l) range and empiric dose adjustment does not improve the results sufficiently. Model-based initial dosage with Bayesian individual dose adjustment seems to be a promising method for improving vancomycin dosing accuracy in neonatal population.
    Vastsündinute populatsioonis on suure farmakokineetilise varieeruvuse tõttu väga raske tagada ravimi optimaalset ekspositsiooni organismis. Julgelt üle 50% ravimi baaskontsentratsioonidest jääb väljaspoole ravi eesmärki (Ctr 10-15mg/l) ning ka doosi kohandamine ei paranda tulemusi piisavalt. Mudelipõhine algdoos ning Bayesi statistikal põhinev individuaalne doosi kohandamine võimaldaks parandada vankomütsiini doseerimistäpsust vastsündinutel.
    E.1.1.1Medical condition in easily understood language
    Individual dosing of Vancomycin in neonates
    Vankomütsiini indiviidipõhine doseerimine vastsündinutel
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    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
    Primary objective
    • To evaluate the validity (accuracy and variability) of vancomycin dosing in neonates with the free software DosOpt to determine whether individual dose optimization gives an advantage over empirical dosing.
    Käesoleva uurimustöö peamine eesmärk on:
    • prospektiivselt valideerida uue Bayesi raamistikul põhineva tarkvara, DosOpt’i, optimeerimistäpsust vastsündinute vankomütsiinravi kohandamisel.
    E.2.2Secondary objectives of the trial
    Secondary objective
    • To demonstrate the safety of dose adjustment with DosOpt in neonates
    • To analyze the impact of each additional TDM measurement to the prediction accuracy and variability in order to give recommendations on TDM routines in neonates
    • To describe the outliers: which demographic features (i.e. PMA, CW, small for gestational age (SGA)) and concomitant diseases (i.e. renal and circulatory status) degrade the prediction capability the most.
    • To describe the patients (i.e PMA, CW, concomitant diseases) who get the most benefit from adjusting dose with DosOpt.
    • To analyze the effect of protein and albumin levels on DosOpt prediction accuracy
    • To get a real work experience with DosOpt and improve the DosOpt user interface.
    Uuringu sekundaarsed eesmärgid
    • Hinnata doosioptimeerimise ohutust DosOpt tarkvaraga (sama või väiksem nefrotoksilisuse ja ototoksilisuse risk võrreldes kontrollgrupi ja kirjanduse andmetega).
    • Analüüsida iga ravimmonitooringu (TDM) käigus mõõdetud Ctr arvesse võtmise mõju doosi optimeerimise täpsusele ning anda seeläbi soovitusi optimaalsemaks ravimmonitooringuks.
    • Kirjeldada patsiente, kes saavad Bayesi meetodil doosi kohandamisest kõige suuremat kasu, leida patsiendipoolseid tunnuseid, mis võimaldaksin need haiged etteulatuvalt ära tunda.
    • Analüüside üldvalgu ja albumiiini taseme mõju DosOpti ennustustäpsusele
    • Saada reaalne töökogemus DosOptiga. Parandada DosOpti kasutajaliidest
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subject inclusion criteria
    1. Postnatal age (PNA) ≥72 hours and ≤ 90 days at the beginning of vancomycin therapy
    2. Vancomycin treatment is indicated at the discretion of the attending physician
    3. Informed consent signed by parent or guardian (prospective intervention group) and/or Ethics and Data protection committee approval in place.
    4. Patient does not participate in other "device"-studies
    1) vanus 72h-90 päeva
    2) vankomütsiinravi näidustus perioodil 02.2019-02.2021
    3) vanemad on andnud informeeritud nõusoleku
    4) pt ei osale samaaegselt teistes „device“-i uuringutes
    E.4Principal exclusion criteria
    Subject exclusion criteria
    1. Not expected to survive over 72 hours from initiation of vancomycin treatment
    2. No informed consent given (if recruiting to DosOpt study group)
    3. Current participation in competitive study, what takes blood tests for research purposes.
    1) Vanem keeldub
    2) Eeldatav eluiga <72h
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint
    The proportion of neonates attaining the narrow trough concentration target range Ctr 10-15 mg/L and clinically accepted target range Ctr 10-20mg/l in the two study arms
    (PTA%Ctr 10-15/ Ctr 10-20= probability of target attainment)
    Esmane tulemusnäitaja: Vastsündinute osakaal, kes saavutab ravimi stabiilses olekus baaskontsentratsiooni eesmärkvahemikku (kitsas eesmärkvahemik Ctr 10-15mg/l, kliiniliselt aktsepteeritav eesmärkvahemik Ctr 10-20mg/l)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every time then trough concentration are measured (every dose adjustment visits, usually after 36-48h)
    Iga kord, kui mõõdetakse ravimi baaskontsentratsiooni (igal doosi kohandamise visiidil, tavaliselt 36-48h järel)
    E.5.2Secondary end point(s)
    Secondary endpoint (only for DosOpt group)
    1. The proportion of neonates, attaining the PD target of AUC/MIC≥ 400 and ≤700 (PTA% AUC/MIC 400-700)
    2. Clinical cure, defined as: reinfection, new infection, microbiologic cure (time to sterile blood culture), time to CRV normalization.

    3. Safety endpoints include :
    a. The description of all adverse events (AE) experienced by infants receiving study drugs.
    Clinical and laboratory AE will be recorded until the end of therapy (EOT) and follow up visits (7 days after the end of therapy) and graded according to the need for a specific medical intervention
    b. Incidence of acute kidney injury (AKI): defined by modified neonatal KDIGO criterias (renal function parameters: diuresis, creatinine, urea, cystatin C will be used)
    c. Ototoxicity: otoacoustic emission (OAE) will be documented from the medical history afterwards. Hearing screening (OAE) should be performed after 34weeks PMA according to local, neonatal hearing screening guidelines.

    4. Practical implementation endpoints include:
    a. Identification, discription and documentation of all errors related to the use of DosOpt in clinical practise and detect the possible sources of errors.
    Teisesed tulemusnäitajad:
    1. vastsündinute osakaal, kes saavutab farmakodünaamilise ravi eesmärgi AUC/MIC 400-700 vahemikus (PTA% AUC/MIC 400-700)
    2. Kliiniline paranemine, mis on defineeritud korduvinfektsiooni, uue infektsiooni, mikrobioloogilise külvi steriliseerumise aja ja CRV normaliseerumise ajaga

    3. Ohutusnäitajad
    a.Kõikide uuringus osalevate patsientide kõrvalnähtude, raskete kõrvalnähtude ning ravimi tõsiste mitteoodatavate kõrvaltoimete dokumenteerimine alates uuringu algusest kuni 7 päeva järelkontrollvisiidini
    b. Ägeda neerukahjustuse hindamine (defineerituna modifitseeritud vastsündinute KDIGO kriteeriumite alusel)
    c. Ototoksilisuse hindamine: kuulmisskriining OAE registreeritakse kõikidel patsientidel vastavalt osakonna rutiinile.

    4. Praktilise rakendamise tulemusnäitajad
    a. Kõigide DosOptiga ettetulevate probleemide tuvastamine, kirjeldamine ja dokumenteerimine.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Each dose adjustment visit
    2. From the start of recruitment until 7 days after treatment (follow up vist)
    3a and 3b From recruitment (V0) to the 7 day follow up vist (V7p)
    3c OAE visit- then hearing screening is performed (depends on child and neonatal unit)
    4a- Each dose optimization visit (from V0-Vn), there n- is the last visit of dose adjustment
    1. Igal doosi kohandamise visiidil (V2-Vn, usually after every 36-48h)
    2. Ravi algusest kuni 7 päeva järelkontrollini
    3a, 3b- patsiendi uuringusse värbamisest kuni 7 päeva järelkontrollini
    3c OAE-teostamise päeval (vastavalt uuringu teostamise ajale)
    4a Igal doosi kohandamise visiidil (Al V0-Vn), kus n- on viimane visiit, kus doosi kohandatakse.
    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 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) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    retrospektiivne kontrollgrupp
    historical control
    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
    standardskeemid, empiiriline doosi kohandamine
    standard of care, empirical dose adjustment
    E.8.2.4Number of treatment arms in the trial2
    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 concerned2
    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
    Last subject last visit
    Viimase uuringupatsiendi viimane visiit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    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 Yes
    F.1.1Number of subjects for this age range: 50
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Yes
    F.1.1.2.1Number of subjects for this age range: 45
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 50
    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) No
    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 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
    Newborns
    Vastsündinud
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    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)
    Follow up 7 days after last dose
    Jälgimisvisiit 7 päeva pärast viimast uuringuravimi annust
    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 Decision2019-05-08
    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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