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    Summary
    EudraCT Number:2016-004451-70
    Sponsor's Protocol Code Number:NOR-GRASPALL-2016
    National Competent Authority:Lithuania - SMCA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-05-08
    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 ConcernedLithuania - SMCA
    A.2EudraCT number2016-004451-70
    A.3Full title of the trial
    NOR-GRASPALL 2016: SINGLE-ARM PHARMACOKINETIC/PHARMACODYNAMIC AND SAFETY STUDY OF ERYASPASE (GRASPA®) FOR PATIENTS WITH HYPERSENSITIVITY TO PEG-ASPARAGINASE, DIAGNOSED WITH PH(-) ACUTE LYMPHOBLASTIC LEUKEMIA
    NOR-GRASPALL 2016: nerandomizuotas vienos šakos klinikinis tyrimas vaistinio praparato eriaspazės (GRASPA®) farmakokinetinėms / farmakodinaminėms savybėms ir saugumui įvertinti, į kurį įtraukiami ligoniai su išsivysčiusiu padidėjusiu jautrumu PEG-asparaginazei ir kuriems diagnozuota ūminė limfoblastinė leukemija
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Eryaspase treatment for children and young adults with leukemia and hypersensitivity to PEG-asparaginase.
    Gydymas eriazpaze vaikų ir jaunų suaugusiųjų, kuriems išsivystė padidėjęs jautrumas PEG-asparaginazei.
    A.3.2Name or abbreviated title of the trial where available
    NOR-GRASPALL 2016
    A.4.1Sponsor's protocol code numberNOR-GRASPALL-2016
    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 SponsorDepartment of pediatrics, Aarhus University Hospital
    B.1.3.4CountryDenmark
    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 supportERYTECH Pharma
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDepartment of pediatrics, Aarhus University Hospital
    B.5.2Functional name of contact pointLine Stensig Lynggaard
    B.5.3 Address:
    B.5.3.1Street AddressPalle Juul-Jensens Boulevard 99
    B.5.3.2Town/ cityAarhus N
    B.5.3.3Post code8200
    B.5.3.4CountryDenmark
    B.5.4Telephone number004525112022
    B.5.6E-mailline.stensig@rm.dk
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/06/409
    D.3 Description of the IMP
    D.3.1Product nameEryaspase (GRASPA)
    D.3.2Product code -
    D.3.4Pharmaceutical form Dispersion for infusion
    D.3.4.1Specific paediatric formulation No
    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 INNL-asparaginase encapsulated in erythrocytes
    D.3.9.1CAS number none
    D.3.9.3Other descriptive nameL-ASPARAGINASE ENCAPSULATED IN ERYTHROCYTES
    D.3.9.4EV Substance CodeSUB181586
    D.3.10 Strength
    D.3.10.1Concentration unit IU/ml international unit(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number78 to 146
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    Patients with acute lymphoblastic leukemia with allergy against PEG-asparaginase
    Ligoniai, gydomi dėl ūminės limfoblastinės leukemijos, kuriems išsivysto alergija PEG-asparaginazei
    E.1.1.1Medical condition in easily understood language
    Patients with cancer (leukemia) and clinical allergy to asparaginase (chemotherapy)
    Ligoniai, gydomi nuo vėžio (leukemijos), kurie netoleruoja gydymo asparaginaze (chemopreparatu)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Main objectives of this study are to evaluate the pharmakinetic and pharmacodynamic profile of eryaspase administered to patients who experience a PEG-asparaginase hypersensitivity event during treatment with the multi-agent NOPHO ALL 2008 chemotherapy for the treatment of children and adult patients with ALL
    Pagrindinis tikslas yra įvertinti eryaspazės, skiriamos gydyti ligoniams, kuriems gydant pagal vaikų ir jaunų suaugusių NOPHO ALL 2008 polichemoterapijos gydymo protokolą išsivysto padidėjusio jautrumo reakcija į PEG-asparaginazę, farmakokinetines ir farmakodinamines savybes.
    E.2.2Secondary objectives of the trial
    Evaluation of the immunogenicity of eryaspase determined by assessment of anti-L-asparaginase-antibodies.
    Evaluation of the overall safety and tolerability of eryaspase in combination with multi-agent chemotherapy (according to NOPHO ALL 2008).
    Finally, the effect of eryaspase on the concurrent maintenance therapy with 6-mercaptopurine and methotrexate will be evaluated.
    Įvertinti eryaspazės imunogeniškumą nustatant prieš L-asparaginazę susidariusių antikūnų titrą.
    Įvertinti bendrą eryaspazės saugumą ir efektyvumą, kai ji skiriama taikant kombinuotą chemoterapiją (pagal NOPHO ALL 2008 protokolą).
    Įvertinti eryazpazės poveikį kartu skiriamam palaikomajam gydymui 6-merkaptopurinu ir metotreksatu.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria:
    1. Male or female aged 1-45 years at diagnosis of ALL
    2. First line non-high risk (HR) ALL patients enrolled in NOPHO ALL 2008 including PEG-asparaginase regimen
    3. Documented hypersensitivity reaction to PEG-asparaginase with either:
    • Clinical allergy to PEG- (mild/severe) OR Serum asparaginase activity below the lower level of quantification
    4. Karnofsky/Lansky score ≥ 50.
    5. Ability to understand, and willingness to sign, a written informed consent document and to comply with the scheduled visits, treatment plans, laboratory tests, and other study procedures. For patients under 18 years of age, either both parents or the legally appointed representatives will need to provide consent.
    Įtraukimo kriterijai:
    1. Vyriškos ar moteriškos lyties 1-45 metų amžiaus asmenys, gydomi dėl ŪLL.
    2. Kaip pirmos eilės gydymą gaunantys ne didelės rizikos šakos gydymą pagal NOPHO ALL 2008 protokolą, turintį savo sudėtyje PEG-asparaginazę.
    3. Dokumentuotas padidėjęs jautrumas PEG-asparaginazei, pasireiškiantis arba klinikine lengvos ar sunkios alergijos PEG-asparaginazei išraiška, arba nustačius mažesnę negu apatinė išmatuojama riba, asparaginazės koncentraciją kraujo serume.
    4. Aktyvumas pagal Karnofsky/Lansky skalę ≥ 50.
    5. Gebėjimas suprasti, noras pasirašyti rašytinę informuoto asmens sutikimo formą ir laikytis nustatytų vizitų, gydymo plano, laboratorinių tyrimų ir kitų tyrimo procedūrų plano. Jeigu ligonis jaunesniems nei 18 m., informuoto asmens sutikimo formą turi pasirašyti abu tėvai arba globėjai.
    E.4Principal exclusion criteria
    Exclusion Criteria:
    1. Philadelphia chromosome positive ALL.
    2. Participation in another clinical trial interfering with the study therapy.
    3. Uncontrolled intercurrent illness including, but not limited to, receiving combination antiretroviral therapy or patients with severe or systemic infection, or psychiatric illness/social situations that would limit compliance with study requirements.
    4. Other severe acute/chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.
    5. Pregnant or lactating females .
    6. Inadequate organ functions, which prohibit further asparaginase administration
    7. History of grade 3 or higher transfusion reactions or any contraindication to receive blood transfusion. Presence of specific anti-erythrocytes antibodies (auto-antibodies or anti-public antibodies) preventing from getting a compatible packed Red Blood Cells for the patient.
    8. Patient under concomitant treatment likely to cause hemolysis.
    Neįtraukimo kriterijai:
    1. Ph+ ŪLL
    2. DAlyvavimas kitame klinikiname tyrime, besikertančiame su atliekamu klinikiniu tyrimu.
    3. Nekontroliuojam gretutinė liga, įskaitant, bet neapsiribojant kombinuotų antiretrovirusinių preparatų vartojimu, arba sunkiomis ar lėtinėmis infekcijomis, arba psichiatrinėmis ligomis ar socialinėmis sąlygomis, kurios galėtų trukdyti tyrimo reikalavimų.
    4. Kitos ūminės / lėtinės būklės ar laboratoriniai sutrikimai, kurie galėtų didinti dalyvavimo tyrime ar vaistinio preparato skyrimo riziką, arba galėtų trukdyti įvertinti tyrimo rezultatus, ir tyrėjo sprendimu būtų netinkamas šiam tyrimui.
    5. Besilaukiančios ar žindančios moterys.
    6. Sutrikusi organų funkcija, galinti neleisti tęsti gydymo asparaginaze.
    7. Išsivysčiusi 3 ar didesnio stiprumo transfuzinė reakcija arba kontraindikacija gauti kraujo komponentų transfuziją. Susidarę specifiniai antikūnai prieš eritrocitus (autoantikūnai arba aloantikūnai), neleidžiantys ligoniui perpilti tapačių eritrocitų masės.
    8. Tyrimo metu gaunant gydymą, potencialiai galintį sukelti hemolizę.
    E.5 End points
    E.5.1Primary end point(s)
    •The safety and tolerability of eryaspase in combination with standard multi-agent NOPHO ALL 2008 chemotherapy assessed during eryaspase treatment period according to potential toxicities defined in "the adverse experience section".
    •Pharmacokinetic parameters:
    Total activity (at time points listed in Section 9.4) will be measured. The main pharmacokinetic parameters will be assessed: Cmax; Tmax; T1/2 (half-life time); Vss (Distribution Volume at steady state), MRT (Mean Residence Time) and clearance.
    Percentage of patients with asparaginase activity >100 IU/L.

    •Pharmacodynamic profile:
    Plasma and CSF concentrations of amino-acids: (asparagine, aspartate, glutamine, glutamate)


    •Immunogenicity: titers of anti-asparaginase antibodies

    • Safety: incidence of hypersensitivity (allergic reactions and silent inactivation) at the end os asparaginase treatment.
    * Įvertinti eryaspazės saugumą ir efektyvumą skiriant eryaspazę su kombinuotu gydymu chemoterapija pagal NOPHO ALL 2008 protokolą; potencialaus toksiškumo eryapazės skyrimo metu vertinimas apibūdintas "pašalinių reakcijų išsivystymo skyriuje"

    * Farmakokinetiniai parametrai: bus matuojamas bendras aktyvumas (9.4 skyriuje aprašytais laikotarpiais). Bus nustatomi pagrindiniai farmakokinetiniai parametrai: Cmax; Tmax; T1/2 (skilimo pusperiodis); Vss (pasiskirstymo tūris pusiausvyros stadijoje); MRT (vidutinis preparato gyvavimo laikas) ir klirensas. Bus nustatomas ligonių, kurių asparaginazės aktyvumas >100 IU/L procentas.

    * Farmakodinaminės savybės: matuojama amino rūgščių (asparagino, aspartato, gliutamino, gliutamato) koncentracijos kraujo serume ir likvore.

    * Imunogeniškumas: antikūnų prieš asparaginazę titras.

    * Saugumas: asparaginazės skyrimo pabaigoje bus vertinamas padidėjusio jautrumo išsivystymas (alerginės reakcijos ir nebyliųjų antikūnų susidarymas).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Inclusion of patients are expected to start in January 2017 and the study will end when 30 patients are included or in January 2020 at the latest. Patients will be followed one year after last administration.
    Į tyrimą ligonius įtraukti planuojama 2017 m. sausį, o baigti tyrimą įtraukus 30 tiriamųjų arba vėliausiai 2020 m. sausį. Ligonių būklė bus sekama vienerius metus po paskutinės dozės.
    E.5.2Secondary end point(s)
    •Secondary endpoints are to evaluate toxicity according to the PdL consensus definitions.
    •Levels of maintenance metabolites
    Įvertinti toksiškumą pagal PdL nustatytas definicijas.
    Nustatyti palaikomojo gydymo preparatų metabolitų koncentracijas.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Inclusion of patients are expected to start in January 2017 and the study will end when 30 patients are included or in January 2020 at the latest. Patients will be followed one year after last administration.
    Į tyrimą ligonius įtraukti planuojama 2017 m. sausį, o baigti tyrimą įtraukus 30 tiriamųjų arba vėliausiai 2020 m. sausį. Ligonių būklė bus sekama vienerius metus po paskutinės dozės.
    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 No
    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 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 No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Vienos šakos, prospektyvus, aprašomasis, daugiacentris, daugianacionalinis
    Single-arm, prospective, descriptive, multicenter,multinational
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Lygiagrečiai kiti ligoniai gaus standartinį gydymą PEG-asparaginaze (pagal NOPHO ALL 2008 protokolą)
    Matched patients having standard therapy with PEG-asparaginase (NOPHO ALL 2008)
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA7
    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
    Paskutinis paskutinio įtraukto tiriamojo vizitas.
    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: 30
    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: 2
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 13
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 5
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    The trial subjects include under aged children (<15 years) who are not allowed to give informed consent themselves. The parents have to give the informed consent on behalf of the child.
    Jaunesni nei 18 metų tiriamieji, kuriems neleidžiama vieniems pairašyti informuoto asmens sutikimo formos. Jiems Informuoto asmens sutikimo forma turės būti pasirašyta abiejų tėvų arba globėjų.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 30
    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)
    Patients will continue ALL treatment according to the NOPHO ALL2008protocol
    Ligoniai toliau bus gydomi pagal NOPHO ALL2008 protokolą.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation NOPHO nordic society of pediatric hematology and oncology
    G.4.3.4Network Country Denmark
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-07-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-11-27
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