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    Summary
    EudraCT Number:2018-000853-29
    Sponsor's Protocol Code Number:TRACE
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-06-24
    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 ConcernedGermany - PEI
    A.2EudraCT number2018-000853-29
    A.3Full title of the trial
    Treatment of chemo-refractory viral infections after allogeneic
    stem cell transplantation with multispecific T cells against CMV, EBV and AdV:
    A phase III, prospective, multicentre clinical trial
    Therapie refraktärer Virusinfektionen nach allogener
    Stammzelltransplantation mit multispezifischen T-Zellen gegen CMV, EBV
    und ADV: eine Phase III, prospektive, multizentrische klinische Studie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of viral infections after stem cell transplantation with specific immune cells
    Bekämpfung von Virusinfektionen nach Stammzelltransplantation mit
    speziellen Abwehrzellen
    A.3.2Name or abbreviated title of the trial where available
    Multivirus-specific T-cell transfer post SCT vs AdV, CMV and EBV infections (TRACE)
    Mulitvirus-spezifischer T-Zell Transfer nach SZT vs AdV, CMV und EBV Infektionen (TRACE)
    A.4.1Sponsor's protocol code numberTRACE
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04832607
    A.5.4Other Identifiers
    Name:DRKSNumber:00018985
    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 SponsorKlinikum der Universität München
    B.1.3.4CountryGermany
    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 supportEuropean Commission
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKlinikum der Universität München - Dr. von Hauner Children's Hospital
    B.5.2Functional name of contact pointPed. Hematology/Oncology, TRACE
    B.5.3 Address:
    B.5.3.1Street AddressLindwurmstrasse 4
    B.5.3.2Town/ cityMunich
    B.5.3.3Post code80337
    B.5.3.4CountryGermany
    B.5.6E-mailonkostudien.hauner@med.uni-muenchen.de
    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/3/15/1438 (AdV), 1439 (CMV) and 1440 (EBV)
    D.3 Description of the IMP
    D.3.1Product nameMultivirus (CMV, EBV, AdV-) specific T cells
    D.3.4Pharmaceutical form 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 INNMultivirus (CMV, EBV, AdV-) specific T cells
    D.3.9.3Other descriptive nameAllogeneic human multivirus specific T cells enriched for specificity against CMV, EBV, AdV
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1000 to 20000000
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    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 Yes
    D.3.11.3.5.1CAT classification and reference numberEMA/277503/2013
    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) Yes
    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 Yes
    D.3.11.13.1Other medicinal product typeHuman multivirus-specific T cells enriched for specificity against Cytomegalovirus, Adenovirus and Epstein-Barr Virus
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboInfusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chemo-refactory AdV, CMV and EBV infections after allogeneic stem cell transplantation
    E.1.1.1Medical condition in easily understood language
    Infections with the viruses AdV, CMV and EBV which occur after stem cell transplantation and could not be successfully treated with available chemotherapy
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.0
    E.1.2Level PT
    E.1.2Classification code 10067859
    E.1.2Term Allogenic stem cell transplantation
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10011831
    E.1.2Term Cytomegalovirus infection
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10060931
    E.1.2Term Adenovirus infection
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10015108
    E.1.2Term Epstein-Barr virus infection
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluation of efficacy of multispecific T-cell transfer in patients with chemo-refractory viral infections after allogeneic stem cell transplantation
    E.2.2Secondary objectives of the trial
    - Incidence and severity of newly occurring GvHD
    - Incidence and severity of acute toxicity
    - Effect on viral load of underlying viral infection
    - Clinical response/resolution of symptoms of underlying viral infection
    - Overall survival
    - Necessity and duration of antiviral chemotherapy
    - Incidence of viral infections other than underlying viral infection: evaluation of putative prophylactic effect of treatment
    - Days of hospitalization
    - Quality of life
    - Effect on the patients’ T-cell immunity in vivo
    - Quality of the IMP and performance of the CliniMACS® Prodigy
    - Evaluation of the drop-out rate
    - Evaluation of time from inclusion to administration of the IMP
    - Overall safety evaluation
    - Concomitant medication
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Adult or paediatric patients (>2 months of age) after HSCT suffering from new or reactivated CMV, EBV or AdV infection and refractory to standard antiviral treatment for two weeks (defined as ≤1 log decrease in viral load over two weeks) as confirmed by quantitative blood PCR analysis
    2. Original HSCT-donor available with an immune response at least to the virus causing the therapy-refractory (underlying) infection
    3. Written informed consent given (patient or legal representative)
    E.4Principal exclusion criteria
    1. Acute GvHD > grade II or extensive chronic GvHD at time of IMP transfer
    2. Treatment with steroids (>1 mg/kg Prednisone equivalent) at Screening
    3. Therapeutic donor lymphocyte infusion (DLI) from 4 weeks prior to IMP infusion until 8 weeks post IMP infusion. In case of T-cell depleted HSCT, a prescheduled prophylactic DLI ≤3 x 10e5 T cells/kg BW is not considered an exclusion criteria.
    4. Organ dysfunction or failure as determined by Karnofsky (age >16 years) or Lansky (age ≤16 years) score ≤30%
    5. Concomitant enrolment in another clinical trial interfering with the endpoints of this study
    6. Any medical condition which could compromise participation in the study according to the investigator’s assessment
    7. Progression of underlying disease (disease that has led to the indication of HSCT, e.g. leukaemia) that will limit the life expectance below the duration of the study
    8. Second line or experimental antiviral treatment other than Ganciclovir/Valganciclovir, Foscarnet, Cidofovir and Rituximab from Screening until 8 weeks after IMP Infusion or prophylactic treatment other than Aciclovir or Letermovir throughout the study except approved by sponsor
    9. Known HIV infection. In case patients do not have a negative HIV test performed within 6 months before enrolment in the study, HIV negativity has to be confirmed by a negative laboratory test.
    10. Female patient who is pregnant or breast-feeding, or adult of reproductive potential not willing to use an effective method of birth control from Screening until the last follow-up visit (FU6, Visit 8) Note: women of childbearing potential must have a negative serum pregnancy test at study entry
    11. Known hypersensitivity to iron dextran
    12. Patients unwilling or unable to comply with the protocol or unable to give informed consent.
    E.5 End points
    E.5.1Primary end point(s)
    - Percentage of patients with viral clearance (defined as two consecutive negative PCRs)
    - Percentage of patients with progression between Day 7 and Week 8 after IMP transfer
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 8 and Week 15
    E.5.2Secondary end point(s)
    - Incidence/severity of acute GvHD ≥ grade II until Week 8 and Week 15.
    - Incidence of newly occurring acute GvHD grade I from Day 0 to Week 8 and Week 15.
    - Incidence of chronic GvHD from Day 7 to Week 8 and to Week 15 after IMP transfer.
    - Time to newly occurring acute and chronic GvHD.
    - Acute toxicity: maximum toxicity on the day of IMP transfer evaluated by measuring vital signs prior to and at different times after the IMP transfer and monitoring of specific adverse events (chills, nausea, vomiting, diarrhoea, abdominal pain, allergic reactions, respiratory dysfunction or headache from 1 hour prior to IMP transfer to 4 hours post infusion).
    - Change in viral load of underlying viral infection as assessed by quantitative PCR analysis of peripheral blood; samples taken weekly from Day 7 to Week 8 after IMP transfer as compared to samples taken at Day 0.
    - Time to 1 log change in viral load.
    - Percentage of patients with ≥1 log decrease in CMV, EBV or AdV viral load at Week 8.
    - Number of reactivations of the underlying viral infection following initial viral clearance until end of follow-up.
    - Number of patients with reduction or clearance of clinical symptoms of underlyingviral infection from Day 7 to Week 8 after IMP transfer as compared to Day 0.
    - Overall survival rate (OS): From Day 0 to end of follow-up.
    - Number of days requiring antiviral chemotherapy after IMP transfer from Day 7 to Week 8 after IMP transfer.
    - Time to last administration of defined antiviral medication or switch to prophylactic treatment from Day 0 to Week 8 after IMP transfer.
    - Number of new viral reactivations (CMV, AdV or EBV) other than the underlying viral infection per patient as assessed by PCR analysis and clinical symptoms throughout the study.
    - Number of days hospitalized after IMP transfer from Day 7 to Week 8.
    - EQ-5D and FACT-BMT for adult patients (≥18 years), and PEDS-QL for paediatric patients (<18 years) at Screening and Week 8.
    - T-cell phenotyping, samples taken at Screening, Day 0 and each visit from Day 7 to Week 15 after IMP transfer.
    Analysis of virus-specific T cells: frequencies of in vivo expanded virus-specific T cells in peripheral blood samples taken at Screening, Day 0, Day 7 to Week 15 after IMP transfer.
    - Assessment of the number and viability of CD3+ cells and percentage of IFN-gamma+ cells and cellular composition in the IMP.
    - Drop-out rate at Day 0 and reasons for drop-out.
    - Number of days from Screening to Day 0 (day of IMP transfer).
    - Documentation of incidence, severity and type of adverse events from Day 0 to Week 8 and serious adverse events throughout the study.
    - Physical examination and vital signs from Screening to Week 8; Karnofsky/Lansky index will be assessed at Screening and at Week 8.
    - Laboratory values for clinical chemistry and haematology from Screening to Week 8.
    - Documentation of all concomitant medication from Screening to Week 8.
    - During follow-up Week 15, only antiviral therapy, immunosuppression and SAE-related concomitant medication as well as chemotherapy will be documented.
    - Non-therapeutic DLI has to be documented as concomitant medication (definition see exclusion criteria).
    - Treatment with T cells after Week 8 will also be documented as concomitant medication.











    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 8 and Week 15
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    E.8.2.3Other No
    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 concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA35
    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 years3
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days13
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days5
    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: 98
    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: 5
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 46
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 47
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 46
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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
    children
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 111
    F.4.2.2In the whole clinical trial 111
    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)
    Local Standard of care.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-01-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-05
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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