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    The EU Clinical Trials Register currently displays   41449   clinical trials with a EudraCT protocol, of which   6808   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .
     
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    Summary
    EudraCT Number:2012-000695-42
    Sponsor's Protocol Code Number:HGB-205
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-12-19
    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 ConcernedFrance - ANSM
    A.2EudraCT number2012-000695-42
    A.3Full title of the trial
    A Phase I/II Open Label Study Evaluating the Safety and Efficacy of Gene Therapy of the β-Hemoglobinopathies (Sickle Cell Anemia and β-Thalassemia Major) by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo with a Lentiviral beta-A-T87Q-Globin Vector (LentiGlobin® BB305 Drug Product)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Essai clinique de Phase I/II évaluant la sécurité et l’efficacité du produit de thérapie génique LentiGlobin BB305 Drug Product dans le traitement de la drépanocytose sévère et la béta-thalassémie majeure.
    A.3.2Name or abbreviated title of the trial where available
    N/A
    A.4.1Sponsor's protocol code numberHGB-205
    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 Sponsorbluebird bio, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportbluebird bio, Inc. (with its wholly owned subsidiary bluebird bio France)
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNUVISAN ONCOLOGY SA
    B.5.2Functional name of contact pointThierry Rousselot, Project Manager
    B.5.3 Address:
    B.5.3.1Street Address18-20 rue Pasteur
    B.5.3.2Town/ cityLe Kremlin Bicetre
    B.5.3.3Post code94278
    B.5.3.4CountryFrance
    B.5.4Telephone number+33(0)145 15 41 03
    B.5.5Fax number+33(0)145 15 40 61
    B.5.6E-mailthierry.rousselot@nuvisan.com
    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 nameLentiGlobin BB305 Drug Product (autologous CD34 cells transduced w/ LentiGlobin BB305)
    D.3.4Pharmaceutical form Suspension for 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 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 No
    D.3.11.3.2Gene therapy medical product Yes
    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/CAT/988303/2011
    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 Yes
    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
    Severe sickle cell anemia and transfusion-dependent beta-thalassemia major.
    This study will enroll patients who are eligible for an allogeneic hematopoietic stem cell transplant (HSCT) but do not have a suitable, willing human leukocyte antigen (HLA)-identical sibling donor.
    E.1.1.1Medical condition in easily understood language
    beta-thalassemia major and severe sickle cell anemia
    beta-thalassemie majeure et drepanocytose severe
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10055579
    E.1.2Term Sickle-cell beta thalassemia
    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
    Determine the safety, tolerability, and success of engraftment with autologous CD34+ hematopoietic stem cells transduced with LentiGlobin® BB305 lentiviral vector encoding the human beta-A-T87Q- globin gene and suspended in Albunorm™ (human serum albumin; HSA) 5% (i.e., LentiGlobin® BB305 Drug Product) after conditioning with Busulfex® (busulfan IV) in subjects with severe sickle cell anemia (SCA) or beta thalassemia major (beta ThalM).
    E.2.2Secondary objectives of the trial
    I - Quantify gene transfer efficiency and expression:
    •Evaluate expression of beta-A-T87Q-globin chain in peripheral blood burst forming units erythroid (BFU-Es), reticulocytes, and red blood cells (RBCs).
    •Quantify the hematopoietic chimerism resulting from treatment with LentiGlobin® BB305 Drug Product (vector copy number [VCN]).

    II - Measure the effects of transplantation with LentiGlobin® BB305 Drug Product on the expression of disease-specific biological parameters and clinical events, including the volume of blood transfusions for both severe sickle cell anemia and beta-thalassemia major and, for subjects with severe sickle cell anemia, the number of vaso-occlusive crises (VOC) and acute chest syndrome (ACS) events in each subject compared with the 2 year pre-treatment period.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    All subjects must:
    1.Be between 5 and 35 years of age, inclusive.
    •Adult subjects (between 18 and 35 years of age, inclusive, at the time of consent) must be able to provide written consent.
    •For pediatric subjects (between 5 and 17 years of age, inclusive, at the time of consent), a competent parent or legal guardian must be able to provide written informed consent. When possible, involvement of the child >7 years of age in the decision is highly recommended, and written assent will be obtained and should be clearly documented.
    •Subjects aged 5 to 14 years require the approval from the Comité de Surveillance prior to enrollment.

    2.Have severe SCA or transfusion dependent beta-ThalM, regardless of the genotype (e.g., β0, β+, βE/β0, βS/βS, βS/β0), with the diagnosis confirmed by Hb studies. Subjects with transfusion dependent beta-ThalM must be stable and maintained on an appropriate iron chelation regimen. Transfusion dependence is defined as requiring at least 100 mL/kg/year of packed RBCs.
    3.Be candidates for HSCT.
    4.Be willing and able, in the Investigator’s opinion, to comply with the study procedures outlined in the study protocol. If a pediatric subject, the subject’s parent/legal guardian also must be willing and able to comply with the study procedures outlined in the study protocol.
    5.Have been treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records, including transfusion history.

    Subjects with severe SCA also must:
    6.Have 1 or more of the following poor prognostic risk factors despite having had adequate therapy (at least 4 months duration) with hydroxyurea (unless they were unable to tolerate hydroxyurea therapy):
    •Recurrent VOC and/or priapism (at least 2 episodes in the preceding year or in the year prior to start of a regular transfusion program).
    •Presence of cerebral vasculopathy requiring a long term transfusion program (at least 6 months).
    •Presence of any significant cerebral abnormality on magnetic resonance imaging (MRI) (such as stenosis or occlusions).
    •Stroke without any severe cognitive disability.
    •Osteonecrosis of 2 or more joints.
    •Red cell alloimmunization (>2 antibodies).
    •Presence of sickle cell cardiomyopathy documented by Doppler echocardiography.
    •Recurrent acute chest syndrome (at least 2 episodes in the preceding year) defined by the presence of a new pulmonary infiltrate involving at least 1 complete lung segment (but excluding atelectasis) associated with at least 1 new symptom: chest pain, fever (>38.5°C), tachypnea, wheezing or cough not explained by infection. Subjects with a chronic oxygen saturation <90% (excluding periods of SCA crisis) or carbon dioxide diffusing capacity (DLco) less than 60% in the absence of an infection should not be included in the study.
    E.4Principal exclusion criteria
    All subjects must not meet any of the following:
    1.Availability of a suitable, willing HLA identical sibling.
    2.Positive for presence of human immunodeficiency virus type 1 or 2 (HIV 1 and HIV 2), human T lymphotrophic virus 1 (HTLV 1), vesicular stomatitis virus G (VSV G) antibody or VSV G ribonucleic acid (RNA).
    3.Clinically significant, active bacterial, viral, or fungal infection.
    4.Contraindication to anesthesia for bone marrow harvesting.
    5.Any prior or current malignancy, myeloproliferative or immunodeficiency disorder.
    6.A white blood cell (WBC) count <3×10^9/L and/or platelet count <120×10^9/L.
    7.Receipt of an allogeneic transplant.
    8.Receipt of erythropoietin within 3 months before HSCT harvest.
    9.Immediate family member with a known or suspected Familial Cancer Syndrome (including but not limited to breast, colorectal, ovarian, prostate, and pancreatic cancers).
    10.Diagnosis of significant psychiatric disorder of the subject that could seriously impede the ability to participate in the study.
    11.History of malaria relapses in the absence of recent infection.
    12.History of complex allo immunization, which could cause difficulty administering transfusions.
    13.Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile subjects. Females of child bearing potential must agree to use a medically acceptable method of birth control such as oral contraceptive, intrauterine device, barrier and spermicide, or contraceptive implant/injection throughout the 27 month study period.
    14.History of major organ damage including:
    •Liver disease, as evidenced by transaminase levels >3× upper limit of normal or the presence of histopathological evidence of liver cirrhosis on liver biopsy.
    •Heart disease, with a left ventricular ejection fraction <25%.
    •Kidney disease with a calculated creatinine clearance <30% normal value.
    •Severe iron overload, which in the opinion of the physician is grounds for exclusion.
    •A cardiac T2* <10 ms by MRI.
    •Evidence of significant pulmonary hypertension.
    15.Any other condition that would render the subject ineligible for HSCT, as determined by the attending transplant physician.
    16.Participation in another clinical study with an investigational drug within 30 days of screening.
    17.Subjects who have the desire to become a parent within the 27 month study period.
    18.Prior receipt of gene therapy.
    19.An assessment by the Investigator that the subject or parents of the subject will not comply with the study procedures outlined in the study protocol.
    Subjects with beta-ThalM also must not:
    Be Pesaro Class III (poor compliance of iron chelation therapy, presence of hepatomegaly, and severe fibrosis) (Lucarelli et al., 2001).
    E.5 End points
    E.5.1Primary end point(s)
    SAFETY ENDPOINTS:
    •Success and kinetics of HSC engraftment.
    •Incidence of transplant related mortality through 100 days post treatment.
    •Overall survival.
    •Detection of vector derived RCL in any subject.
    •Characterization of events of insertional mutagenesis leading to clonal dominance or leukemia.
    •Monitoring of laboratory parameters and frequency and severity of clinical adverse events (AEs), as assessed by the United States (US) National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03

    EFFICACY ENDPOINTS:
    The effects on the expression of disease specific biological parameters and clinical events will be measured, as follows:

    For all subjects:
    •RBC transfusion requirements (measured in milliliters [mL] per kilogram [kg]) per month and per year post transplant.
    •Number of total in patient hospitalization days (post transplant discharge) at 6, 12, and 24 months.

    For subjects with severe SCA only:
    •Evaluation of cerebral vasculopathy at 6, 12, and 24 months.
    •Number of VOC or acute chest syndrome events at 6, 12, and 24 months.
    •Evaluation of changes in the nature or frequency of the subject specific main inclusion criteria.

    PHARMACODYNAMIC ENDPOINTS:
    To quantify both gene transfer efficiency and expression by measuring the following:
    •Therapeutic globin expression, as measured by assessing the ratio of βA T87Q globin to αlpha globin in BFU-Es, reticulocytes, and red blood cells, as well as the amount of βA T87Q globin as a fraction of all β chains in RBCs. (In the absence of transfusions for a minimum of 3 months, βA T87Q globin will be assessed only in RBCs.)
    •Average VCN in cell populations from peripheral blood and bone marrow containing the integrated LentiGlobin® BB305 lentiviral vector.
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 months
    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 No
    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) Yes
    E.7.1.1First administration to humans Yes
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial1
    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.8.5.1Number of sites anticipated in the EEA2
    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
    The study will end when the last subject completes the Month 24 visit or discontinues from the study.
    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
    E.8.9.2In all countries concerned by the trial years4
    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: 3
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 1
    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: 4
    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 No
    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 state7
    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 completion of HGB-205, subjects will be followed for long term safety and efficacy under a separate protocol for 13 years. Thus, subjects will be followed for a total of 15 years post-transplant.
    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 Decision2012-12-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-12-31
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-02-26
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