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    Summary
    EudraCT Number:2013-004953-26
    Sponsor's Protocol Code Number:BHS-TC13
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-03-21
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2013-004953-26
    A.3Full title of the trial
    CMV specific T cell therapy for the treatment of relapsing or therapy refractory CMV infection after allogeneic stem cell transplantation with a CMV-positive donor.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    CMV specific T cell therapy for the treatment of relapsing or therapy refractory CMV infection after allogeneic stem cell transplantation with a CMV-positive donor.
    A.4.1Sponsor's protocol code numberBHS-TC13
    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 SponsorGhent University Hospital
    B.1.3.4CountryBelgium
    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 supportSpeerpunt Immunologie UZ Gent
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGhent University Hospital
    B.5.2Functional name of contact pointBimetra Clinics
    B.5.3 Address:
    B.5.3.1Street AddressDe Pintelaan 185
    B.5.3.2Town/ cityGhent
    B.5.3.3Post code9000
    B.5.3.4CountryBelgium
    B.5.4Telephone number+3293320500
    B.5.5Fax number+3293320520
    B.5.6E-mailbimetra.clinics@uzgent.be
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namedonor derived antiviral T cells (CMV)
    D.3.4Pharmaceutical form Suspension for injection
    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 INNDonor Derived Anti-viral T cells (CMV)
    D.3.9.3Other descriptive nameHUMAN CYTOMEGALOVIRUS IMMUNOGLOBULINS
    D.3.9.4EV Substance CodeSUB14189MIG
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1000 to 25000
    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 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
    CMV specific T cell therapy for the treatment of relapsing or therapy refractory CMV infection after allogeneic stem cell transplantation with a CMV-positive donor.
    E.1.1.1Medical condition in easily understood language
    CMV specific T cell therapy for the treatment of relapsing or therapy refractory CMV infection after allogeneic stem cell transplantation with a CMV-positive donor.
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    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
    • The primary objective of this clinical trial is double.
    • First, starting from the patients and donors that fulfill all inclusion criteria and do not have any exclusion criterium, and donors fulfilling all pre-apheresis criteria (including a sufficient number of circulating CMV-specific T-cells, based on the in vitro test described below), we will evaluate the percentage of patients for whom we can manufacture a product that meets release criteria, and can therefore receive the product.
    • Second, we will evaluate the safety of the administered cell product. We want to evaluate the frequency of patients who develop de novo or recurrent (with a history of (completely recovered)) acute GVHD grade 2 or more or show worsening of an existing aGVHD with at least 1 grade, or emergence of an additional organ involved.
    E.2.2Secondary objectives of the trial
    • To evaluate the clinical efficacy of this treatment in these patients.
    • To evaluate infusion related toxicity of the infused T cells, within the first 48 hours after infusion.
    • To explore the relationship between the presence of CMV specific T cells in the peripheral blood of the patient and the objective clinical response.
    • To make the treatment of relapsing or refractory CMV infection after allogeneic stem cell transplantation with CMV-specific T cell therapy from the CMV positive donor available for patients in Belgium
    • To compare resistance to antiviral therapy in both arms (investigational vs observational).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients
    o Disease and disease characteristics: all patients with underlying diseases that form an indication for allogeneic stem cell transplantation.
    o Major inclusion criteria:
     Male or female; fertile patients must use a reliable contraception method
     Age 16-75 yrs (the goal is to extend this study in a later stage to children <16yrs, but this will be submitted as an amendment to this trial or as a new clinical trial, depending on the accrual rate and interim analysis)
     Underwent allogeneic stem cell transplantation with a donor that fulfills the following criteria:
    o CMV-seropositive donor (at the time of transplant)
    o Age 18-70 yrs
     Having a CMV reactivation or primary infection (in case of a CMV negative patient pre transplant) or disease (with symptoms, including fever and/or symptoms of organ involvement, eg lungs or intenstine) with the following characteristics
    o CMV PCR at least twice positive AND
    o CMV infection relapsing after 3 successful treatment episodes with gancyclovir (first choice and only reimbursed treatment in Belgium) OR
    o Refractory to treatment with available antiviral drugs (ganciclovir, valganciclovir, foscarnet or combinations - valganciclovir, foscarnet are not reimbursed for this indication in Belgium, so treatment is only possible through medical need programs or after special consent of the mutuality, which is only seldom possible), which is defined as follows:
     Persistent positive CMV PCR > detection limit 14 days after initiation of antiviral treatment or
     Increasing CMV viral load 7 days after initiation of antiviral treatment or
     Informed consent given by patient or his/her guardian if indicated.

    Donor
    1. Donor is identical to donor of the previous stem cell transplant
    2. Donor has positive IgG serology for CMV, IgM negative or positive
    3. Donor has signed informed consent for the donation of donor lymphocyte cells (available worldwide)
    4. Donor is found fit for donation by a medical doctor according to selection criteria conform KB annex II (C-2009/18414)
    5. Donor is negative for infectious disease markers including HCV, HBV and HIV-NAT testing: HBs antigen, HBc/HBs antibodies, Syphilis (TPHA or equivalent), HCV and HIV antibodies.
    6. Additional testing should be performed and negative when relevant: malaria, west nile virus, trypanosomiasis, HTLV conform KB annex II (C-2009/18414)
    In addition, the donor will be pre-screened for the presence of sufficient numbers of CMV-specific T cells.:
    1. Interferon-gamma producing T cells upon CMVpp65 stimulation are at least twice background levels (=unstimulated cells)
    2. At least 10 events of Interferon-gamma positive T cells are measured
    3. Interferon-gamma producing T cells upon CMVpp65 stimulation are equal or higher than 0.1% of the viable CD4+ and CD8+ cell population
    E.4Principal exclusion criteria
    For the patients
    - Any condition not fulfilling inclusion criteria
    - HIV, HCV, HBV positive (of course patients who are HbSAg positive after vaccination are not excluded)
    - Life expectancy severely limited by disease other than malignancy or viral infection;
    - Administration of cytotoxic agent(s) for “cytoreduction” within three weeks prior to initiating of the treatment or to be expected within 8 weeks after administration of the treatment
    - Terminal organ failure (specific detailed descriptions for cardiac, pulmonary and hepatic failure available), except for renal failure (dialysis acceptable)
    - Uncontrolled other infection than the one being treated
    - Karnofsky Performance Score <60%
    - Patient is a fertile man or woman who is unwilling to use contraceptive techniques during and for 12 months following treatment
    - Patient is a female who is pregnant or breastfeeding
    - Patient with active aGVHD grade 3 or more
    - Patient with severe chronic GVHD
    - Patient on corticosteroids > 0.5 mg/kg. Patient can still be on therapeutic doses of immunosuppressive therapy, but these will be tapered to the lowest possible dose, as is part of standard care in case of CMV reactivation.
    - Patient that has received ATG <1m prior to infusion or Campath <1y prior to infusion.

    For the donors
    o Any condition not fulfilling inclusion criteria
    E.5 End points
    E.5.1Primary end point(s)
    • We have identified 2 primary endpoints.
    • First, we have set up a technical endpoint. Starting from the patients and donors that fulfill all inclusion criteria and do not have any exclusion criterium, and donors fulfilling all pre-apheresis criteria (including a sufficient number of circulating CMV-specific T-cells, based on the in vitro test described below), we want to evaluate the percentage of products that meet release criteria, and can therefore be administered to the patient.
    • Second, we have identified a safety endpoint. We will evaluate the frequency of patients developing de novo or recurrent (with a history of (completely recovered)) acute GVHD grade 2 or more or worsening of an existing aGVHD with at least 1 grade, or emergence of an additional organ involved.
    E.5.1.1Timepoint(s) of evaluation of this end point
    up to 1 year after administration
    E.5.2Secondary end point(s)
    • To evaluate the clinical efficacy of this treatment in eligible patients having eligible donors, by comparing outcome in both investigational and observational arm, as evidenced by:
    - Initial response:
    o significant effect (decrease in CMV PCR with at least 1 log on at least 2 consecutive measurements) or
    o complete resolution of the CMV infection (CMV PCR below detection limit for at least 2 consecutive times)
    - Duration of the response (after 1month, 3 months, 6 months and 1 year): the incidence of reactivation of CMV infection after the first good response after T cell administration, which will reflect the in vivo longevity of the administered cells.
    - Duration of antiviral therapy (total duration and starting from the inclusion in the observational vs investigational arm, respectively).
    - Prevention of new reactivations (frequency of reactivations and duration of reactivation/CMV PCR positivity).
    • To evaluate the infusional toxicity of the infused T cells, within the first 72 hours after infusion: clinically (symptoms and clinical signs by means of a check list) and lab results): fever, cytokine storm.
    • To explore the relationship between the presence (and expansion) of CMV specific T cells (absolute number) in the peripheral blood of the patient and the objective clinical response, as measured on week 1, 4 and 8 post infusion.
    • To compare resistance to antiviral therapy in both arms (investigational vs observational).
    E.5.2.1Timepoint(s) of evaluation of this end point
    up to 1 year after administration
    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 No
    E.6.5Efficacy No
    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) 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.8.3 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 concerned8
    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 years6
    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: 2
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 2
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 12
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    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)
    none - standard care
    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 Decision2015-03-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-03-11
    P. End of Trial
    P.End of Trial StatusOngoing
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