<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03240731</url>
  </required_header>
  <id_info>
    <org_study_id>DREPHAPLO</org_study_id>
    <nct_id>NCT03240731</nct_id>
  </id_info>
  <brief_title>HLA Haploidentical Bone Marrow Transplant in Patients With Severe Sickle Cell Disease</brief_title>
  <acronym>DREPHAPLO</acronym>
  <official_title>Bone Marrow Transplantation HLA Haploidentical After a Reduced Intensity Conditioning and Prevention of GvHD Based on Post-transplant Cyclophosphamide Administration in Patients With Severe Sickle Cell Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centre Hospitalier Intercommunal Creteil</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Keocyt</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Association Clinique Thérapeutique Infantile du val de Marne</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Centre Hospitalier Intercommunal Creteil</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      multicentric interventional biomedical research phase II, prospective, non-randomized&#xD;
      evaluating a haploidentical marrow transplants after reduced-intensity conditioning and&#xD;
      prevention of GvHD based on cyclophosphamide administration post transplantation in patients&#xD;
      with severe sickle cell disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Sickle cell disease is a severe disease with frequent occurrence of painful crises and&#xD;
      progressive installation of a multi organ injuries. Despite the progress in its management,&#xD;
      particularly since the introduction of hydroxycarbamide, the median age of death in sickle&#xD;
      cell patients was about 40 years in a recent US study. Severe forms resistant to hydroxyurea&#xD;
      or cerebral vasculopathy require transfusion programs throughout susceptible to risks of iron&#xD;
      overload and alloimmunization. The bone marrow transplantation cures almost 95% of children&#xD;
      and adolescents transplant from an HLA-identical siblings. In patients without HLA-identical&#xD;
      donor, interesting results have been reported in haploidentical transplants marrow without ex&#xD;
      vivo T cell depletion taken after non myeloablative conditioning regimen and GvHD prevention&#xD;
      with cyclophosphamide high dose injection after bone marrow transplant . This approach&#xD;
      performed in 14 patients was effective to cure 50% of the patients and 50% have rejected the&#xD;
      transplant . No death or severe GvHD were related to the procedure.&#xD;
&#xD;
      DREPHAPLO protocol aims to evaluate that approach in a population of sickle cell patients&#xD;
      with severe complications of the disease, bringing direct benefit to patients with a cure of&#xD;
      the disease in at least half of them.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 10, 2017</start_date>
  <completion_date type="Anticipated">September 2025</completion_date>
  <primary_completion_date type="Anticipated">March 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Haploidentical Marrow Transplants</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Survival rate</measure>
    <time_frame>2 years</time_frame>
    <description>Survival without sickle cell survival rate (electrophoresis of hemoglobin similar to that from the donor, that is to say a percentage of HbS not exceeding 10% of that of distance donor transfusions and that of a stable manner and without GvHDc other than mild</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Survival rate</measure>
    <time_frame>1 year</time_frame>
    <description>Survival without sickle cell survival rate (electrophoresis of hemoglobin similar to that from the donor, that is to say a percentage of HbS not exceeding 10% of that of distance donor transfusions and that of a stable manner and without GvHDc other than mild</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>haematologic reconstitution</measure>
    <time_frame>2 years</time_frame>
    <description>defined as a neutrophil count&gt; 500 / mm3 and platelets&gt; 20000 / mm3, for three consecutive days.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chimerism</measure>
    <time_frame>at month 1</time_frame>
    <description>Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chimerism</measure>
    <time_frame>at month 2</time_frame>
    <description>Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chimerism</measure>
    <time_frame>at month 3</time_frame>
    <description>Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chimerism</measure>
    <time_frame>at month 4</time_frame>
    <description>Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chimerism</measure>
    <time_frame>at month 5</time_frame>
    <description>Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chimerism</measure>
    <time_frame>at month 6</time_frame>
    <description>Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chimerism</measure>
    <time_frame>at month 9</time_frame>
    <description>Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chimerism</measure>
    <time_frame>at month 12</time_frame>
    <description>Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chimerism</measure>
    <time_frame>at month 24</time_frame>
    <description>Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>hemoglobin electrophoresis</measure>
    <time_frame>at 1 month</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>hemoglobin electrophoresis</measure>
    <time_frame>at 2 month</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>hemoglobin electrophoresis</measure>
    <time_frame>at 3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>hemoglobin electrophoresis</measure>
    <time_frame>at 4 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>hemoglobin electrophoresis</measure>
    <time_frame>at 5 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>hemoglobin electrophoresis</measure>
    <time_frame>at 6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>hemoglobin electrophoresis</measure>
    <time_frame>at 9 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>hemoglobin electrophoresis</measure>
    <time_frame>at 12 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>hemoglobin electrophoresis</measure>
    <time_frame>at 24 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>occurence of graft versus host disease</measure>
    <time_frame>at month 24</time_frame>
    <description>evaluated monthly from M1 to M6, and M9, M12, M24</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>grade of graft versus host disease</measure>
    <time_frame>at month 24</time_frame>
    <description>Incidence and grade of GvHD, toxic deaths and infectious complications and secondary cancer</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>occurrence of toxic deaths</measure>
    <time_frame>at month 24</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>occurrence of infectious complications</measure>
    <time_frame>at month 24</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>occurrence of secondary cancer</measure>
    <time_frame>at month 24</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lymphocyte immunophenotyping</measure>
    <time_frame>2 years</time_frame>
    <description>Lymphocyte immunophenotyping T, B and NK + The Extended Phenotype including activation markers, assessment of naive people and memories, T reg populations etc) and plasma protein electrophoresis: 1 month, 3 months, 6 months, 12 months and 24 months post-transplantation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ECOG score value</measure>
    <time_frame>2 years</time_frame>
    <description>Index Trading ECOG complete physical examination with determination of weight</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of sickle cell disease complications</measure>
    <time_frame>at 1 year</time_frame>
    <description>Microalbuminuria, creatinuria; echocardiography for measurement of systolic ventricular ejection fraction (February), PAH research and measurement IT Vmax; respiratory function tests with measurement of DLCO; MRI brain with ARM and Cervical Pre-transplant anomalies; Radio of the pelvis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ferritin dosage</measure>
    <time_frame>at month 3</time_frame>
    <description>Evaluation of iron overload by ferritin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ferritin dosage</measure>
    <time_frame>at month 6</time_frame>
    <description>Evaluation of iron overload by ferritin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MRI iron overload</measure>
    <time_frame>at 12 months</time_frame>
    <description>hepatic and cardiac MRI to assess the iron overload</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">18</enrollment>
  <condition>Sickle Cell Disease</condition>
  <arm_group>
    <arm_group_label>bone marrow transplant</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All the included patient will receive an haploidentical bone marrow transplant with the following protocol concerning the conditioning and GvHD prevention&#xD;
Conditioning&#xD;
THYMOGLOBULINE : 0.5mg/kg at D-9 and 2 mg/kg at D-8 and D-7&#xD;
THIOTEPA: 10mg/kg/j at D-7&#xD;
CYCLOPHOSPHAMIDE (Endoxan®):14.5mg/kg/j at D-6 and D-5&#xD;
FLUDARABINE (Fludara®): 30mg/m2 per Day from D-6 to D-2&#xD;
TBI : 2GY : D -1 Graft : Injection at D0 of G-CSF-stimulated bone marrow transplant.&#xD;
Prophylaxis of GvHD&#xD;
CYCLOPHOSPHAMIDE (Endoxan®): 50mg/Kg per Day from D+3 to D+4&#xD;
Sirolimus and MycophénolateMofétil (MMP) from D+5. In the absence of acute GvHD (aGvHD), stop of MMP to D35 and pursuit of sirolimus 1 year after the graft.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>bone marrow transplant</intervention_name>
    <description>haploidentical bone marrow transplant</description>
    <arm_group_label>bone marrow transplant</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria recipient:&#xD;
&#xD;
          -  Age: 13 years-40 years&#xD;
&#xD;
          -  Severe Sickle cell with at least one of the following criteria:&#xD;
&#xD;
               -  Stenosing vasculopathy with abnormal MRA despite prolonged transfusion program&#xD;
&#xD;
               -  PAH confirmed by right catheterization with mPAP&gt; 25mmHg&#xD;
&#xD;
               -  Systolic ejection fraction &lt;55% and tricuspid regurgitation speed&gt; 2.5m /s at&#xD;
                  distance from an acute episode&#xD;
&#xD;
               -  No possibility of blood transfusion or very complicated blood transfusion&#xD;
&#xD;
               -  Report albumin / creatinine&gt; 30 mg / mmol, confirmed 3 times, away at distance&#xD;
                  from acute episode and persistent despite hydroxyurea or IEC&#xD;
&#xD;
               -  GFR &lt;80ml / min /1.73m2 (CKD-Epi without ethnic criterion)&#xD;
&#xD;
               -  Previous history of acute liver sequestration with liver failure&#xD;
&#xD;
               -  Acute chest syndrome or vaso-occlusive crises under hydroxyurea&#xD;
&#xD;
               -  Complications of sickle cell transfusion imposing an exchange program with no&#xD;
                  possible withdrawal beyond a period of one year&#xD;
&#xD;
          -  Not having geno-identical donor, but a haploidentical major donor (parent, sibling,&#xD;
             adult child, or HbAA AS)&#xD;
&#xD;
          -  Having red and understood the information letter and signed the informed consent&#xD;
&#xD;
          -  Patients affiliated to a social security system (Social Security or Universal Medical&#xD;
             Coverage)&#xD;
&#xD;
        Exclusion Criteria recipient:&#xD;
&#xD;
          -  Patient with a geno-identical donor&#xD;
&#xD;
          -  Performans status: ECOG&gt; 1&#xD;
&#xD;
          -  lung disease: FEV1 and FVC &lt;50% predicted,&#xD;
&#xD;
          -  score of PAH NYHA≥2&#xD;
&#xD;
          -  Liver disease with bilirubin&gt; 50 .mu.mol / L&#xD;
&#xD;
          -  heart failure defined by NYHA≥3 score ejection fraction &lt;45% or shortening fraction&#xD;
             &lt;24%&#xD;
&#xD;
          -  anti HLA alloimmunization against the donor or against red cell antigens of the donor&#xD;
&#xD;
          -  Serology or HIV viral load positively&#xD;
&#xD;
          -  Patients who for family, social or geographical reasons, do not wish to be regularly&#xD;
             monitored in consultation&#xD;
&#xD;
          -  severe uncontrolled infection at the time of inclusion or graft&#xD;
&#xD;
          -  pregnant woman (positive beta HCG) or during lactation&#xD;
&#xD;
          -  incapable adult patient, trust, guardianship, or safeguard justice&#xD;
&#xD;
        Inclusion criteria donor&#xD;
&#xD;
          -  Age&gt; 18 years and &lt;60 years&#xD;
&#xD;
          -  Viral serologic economy allows the graft&#xD;
&#xD;
          -  No contraindication for general anesthesia&#xD;
&#xD;
          -  No contraindication the administration of G-CSF (the existence of sickle cell trait is&#xD;
             not a contraindication)&#xD;
&#xD;
          -  Lack antigens HLA recognized by the recipient antibody&#xD;
&#xD;
          -  Hemoglobin S &lt;50%&#xD;
&#xD;
          -  When several donors are compatible: choose according to the ABO recipient: prefer ABO&#xD;
             compatibility and major incompatibility and minor incompatibility, and finally major&#xD;
             and minor incompatibility.&#xD;
&#xD;
          -  Signature of informed consent&#xD;
&#xD;
          -  Non-inclusion criteria donors: β HCG positive or known pregnancy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>13 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>CHU Henri-Mondor</name>
      <address>
        <city>Créteil</city>
        <zip>94000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>intercommunal hospital of Créteil</name>
      <address>
        <city>Créteil</city>
        <zip>94000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU La Timone</name>
      <address>
        <city>Marseille</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Necker</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Robert-Debré</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint-Louis hospital</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Strasbourg</name>
      <address>
        <city>Strasbourg</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
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    <citation>Ciurea SO, Mulanovich V, Saliba RM, Bayraktar UD, Jiang Y, Bassett R, Wang SA, Konopleva M, Fernandez-Vina M, Montes N, Bosque D, Chen J, Rondon G, Alatrash G, Alousi A, Bashir Q, Korbling M, Qazilbash M, Parmar S, Shpall E, Nieto Y, Hosing C, Kebriaei P, Khouri I, Popat U, de Lima M, Champlin RE. Improved early outcomes using a T cell replete graft compared with T cell depleted haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2012 Dec;18(12):1835-44. doi: 10.1016/j.bbmt.2012.07.003. Epub 2012 Jul 11.</citation>
    <PMID>22796535</PMID>
  </reference>
  <reference>
    <citation>Raiola AM, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F, Bregante S, Van Lint MT, Geroldi S, Luchetti S, Ballerini F, Miglino M, Varaldo R, Bacigalupo A. Unmanipulated haploidentical bone marrow transplantation and posttransplantation cyclophosphamide for hematologic malignancies after myeloablative conditioning. Biol Blood Marrow Transplant. 2013 Jan;19(1):117-22. doi: 10.1016/j.bbmt.2012.08.014. Epub 2012 Aug 29.</citation>
    <PMID>22940057</PMID>
  </reference>
  <reference>
    <citation>Kanakry CG, Ganguly S, Zahurak M, Bolanos-Meade J, Thoburn C, Perkins B, Fuchs EJ, Jones RJ, Hess AD, Luznik L. Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide. Sci Transl Med. 2013 Nov 13;5(211):211ra157. doi: 10.1126/scitranslmed.3006960.</citation>
    <PMID>24225944</PMID>
  </reference>
  <reference>
    <citation>Ganguly S, Ross DB, Panoskaltsis-Mortari A, Kanakry CG, Blazar BR, Levy RB, Luznik L. Donor CD4+ Foxp3+ regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice. Blood. 2014 Sep 25;124(13):2131-41. doi: 10.1182/blood-2013-10-525873. Epub 2014 Aug 18.</citation>
    <PMID>25139358</PMID>
  </reference>
  <reference>
    <citation>Stem Cell Trialists' Collaborative Group. Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol. 2005 Aug 1;23(22):5074-87. doi: 10.1200/JCO.2005.09.020.</citation>
    <PMID>16051954</PMID>
  </reference>
  <reference>
    <citation>Yang JZ, Zhang JQ, Sun LX. Mechanisms for T cell tolerance induced with granulocyte colony-stimulating factor. Mol Immunol. 2016 Feb;70:56-62. doi: 10.1016/j.molimm.2015.12.006. Epub 2015 Dec 17.</citation>
    <PMID>26703218</PMID>
  </reference>
  <reference>
    <citation>Jun HX, Jun CY, Yu ZX. In vivo induction of T-cell hyporesponsiveness and alteration of immunological cells of bone marrow grafts using granulocyte colony-stimulating factor. Haematologica. 2004 Dec;89(12):1517-24.</citation>
    <PMID>15590404</PMID>
  </reference>
  <reference>
    <citation>Deotare U, Al-Dawsari G, Couban S, Lipton JH. G-CSF-primed bone marrow as a source of stem cells for allografting: revisiting the concept. Bone Marrow Transplant. 2015 Sep;50(9):1150-6. doi: 10.1038/bmt.2015.80. Epub 2015 Apr 27.</citation>
    <PMID>25915812</PMID>
  </reference>
  <reference>
    <citation>Couban S, Messner HA, Andreou P, Egan B, Price S, Tinker L, Meharchand J, Forrest DL, Lipton J. Bone marrow mobilized with granulocyte colony-stimulating factor in related allogeneic transplant recipients: a study of 29 patients. Biol Blood Marrow Transplant. 2000;6(4A):422-7. doi: 10.1016/s1083-8791(00)70033-4.</citation>
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  </reference>
  <reference>
    <citation>Isola L, Scigliano E, Fruchtman S. Long-term follow-up after allogeneic granulocyte colony-stimulating factor--primed bone marrow transplantation. Biol Blood Marrow Transplant. 2000;6(4A):428-33. doi: 10.1016/s1083-8791(00)70034-6.</citation>
    <PMID>10975511</PMID>
  </reference>
  <reference>
    <citation>Ji SQ, Chen HR, Wang HX, Yan HM, Pan SP, Xun CQ. Comparison of outcome of allogeneic bone marrow transplantation with and without granulocyte colony-stimulating factor (lenograstim) donor-marrow priming in patients with chronic myelogenous leukemia. Biol Blood Marrow Transplant. 2002;8(5):261-7. doi: 10.1053/bbmt.2002.v8.pm12064363.</citation>
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    <citation>Morton J, Hutchins C, Durrant S. Granulocyte-colony-stimulating factor (G-CSF)-primed allogeneic bone marrow: significantly less graft-versus-host disease and comparable engraftment to G-CSF-mobilized peripheral blood stem cells. Blood. 2001 Dec 1;98(12):3186-91. doi: 10.1182/blood.v98.12.3186.</citation>
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    <citation>Serody JS, Sparks SD, Lin Y, Capel EJ, Bigelow SH, Kirby SL, Gabriel DA, Wiley JM, Brecher ME, Schell MJ, Folds J, Shea TC. Comparison of granulocyte colony-stimulating factor (G-CSF)--mobilized peripheral blood progenitor cells and G-CSF--stimulated bone marrow as a source of stem cells in HLA-matched sibling transplantation. Biol Blood Marrow Transplant. 2000;6(4A):434-40. doi: 10.1016/s1083-8791(00)70035-8.</citation>
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  </reference>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>July 31, 2017</study_first_submitted>
  <study_first_submitted_qc>August 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 7, 2017</study_first_posted>
  <last_update_submitted>September 5, 2023</last_update_submitted>
  <last_update_submitted_qc>September 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Saint-Louis Hospital, Paris, France</investigator_affiliation>
    <investigator_full_name>Nathalie Dhédin</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>sickle cell disease</keyword>
  <keyword>haploidentical</keyword>
  <keyword>graft</keyword>
  <keyword>marrow</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia, Sickle Cell</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03240731
org study id: DREPHAPLO
nct id: NCT03240731
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
multicentric interventional biomedical research phase II, prospective, non-randomized
      evaluating a haploidentical marrow transplants after reduced-intensity conditioning and
      prevention of GvHD based on cyclophosphamide administration post transplantation in patients
      with severe sickle cell disease.
Sickle cell disease is a severe disease with frequent occurrence of painful crises and
      progressive installation of a multi organ injuries. Despite the progress in its management,
      particularly since the introduction of hydroxycarbamide, the median age of death in sickle
      cell patients was about 40 years in a recent US study. Severe forms resistant to hydroxyurea
      or cerebral vasculopathy require transfusion programs throughout susceptible to risks of iron
      overload and alloimmunization. The bone marrow transplantation cures almost 95% of children
      and adolescents transplant from an HLA-identical siblings. In patients without HLA-identical
      donor, interesting results have been reported in haploidentical transplants marrow without ex
      vivo T cell depletion taken after non myeloablative conditioning regimen and GvHD prevention
      with cyclophosphamide high dose injection after bone marrow transplant . This approach
      performed in 14 patients was effective to cure 50% of the patients and 50% have rejected the
      transplant . No death or severe GvHD were related to the procedure.

      DREPHAPLO protocol aims to evaluate that approach in a population of sickle cell patients
      with severe complications of the disease, bringing direct benefit to patients with a cure of
      the disease in at least half of them.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Haploidentical Marrow Transplants
primary purpose: Other
masking: None (Open Label)
measure: Survival rate
time frame: 2 years
description: Survival without sickle cell survival rate (electrophoresis of hemoglobin similar to that from the donor, that is to say a percentage of HbS not exceeding 10% of that of distance donor transfusions and that of a stable manner and without GvHDc other than mild
measure: Survival rate
time frame: 1 year
description: Survival without sickle cell survival rate (electrophoresis of hemoglobin similar to that from the donor, that is to say a percentage of HbS not exceeding 10% of that of distance donor transfusions and that of a stable manner and without GvHDc other than mild
measure: haematologic reconstitution
time frame: 2 years
description: defined as a neutrophil count> 500 / mm3 and platelets> 20000 / mm3, for three consecutive days.
measure: Chimerism
time frame: at month 1
description: Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
measure: Chimerism
time frame: at month 2
description: Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
measure: Chimerism
time frame: at month 3
description: Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
measure: Chimerism
time frame: at month 4
description: Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
measure: Chimerism
time frame: at month 5
description: Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
measure: Chimerism
time frame: at month 6
description: Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
measure: Chimerism
time frame: at month 9
description: Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
measure: Chimerism
time frame: at month 12
description: Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
measure: Chimerism
time frame: at month 24
description: Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
measure: hemoglobin electrophoresis
time frame: at 1 month
measure: hemoglobin electrophoresis
time frame: at 2 month
measure: hemoglobin electrophoresis
time frame: at 3 months
measure: hemoglobin electrophoresis
time frame: at 4 months
measure: hemoglobin electrophoresis
time frame: at 5 months
measure: hemoglobin electrophoresis
time frame: at 6 months
measure: hemoglobin electrophoresis
time frame: at 9 months
measure: hemoglobin electrophoresis
time frame: at 12 months
measure: hemoglobin electrophoresis
time frame: at 24 months
measure: occurence of graft versus host disease
time frame: at month 24
description: evaluated monthly from M1 to M6, and M9, M12, M24
measure: grade of graft versus host disease
time frame: at month 24
description: Incidence and grade of GvHD, toxic deaths and infectious complications and secondary cancer
measure: occurrence of toxic deaths
time frame: at month 24
measure: occurrence of infectious complications
time frame: at month 24
measure: occurrence of secondary cancer
time frame: at month 24
measure: Lymphocyte immunophenotyping
time frame: 2 years
description: Lymphocyte immunophenotyping T, B and NK + The Extended Phenotype including activation markers, assessment of naive people and memories, T reg populations etc) and plasma protein electrophoresis: 1 month, 3 months, 6 months, 12 months and 24 months post-transplantation.
measure: ECOG score value
time frame: 2 years
description: Index Trading ECOG complete physical examination with determination of weight
measure: Assessment of sickle cell disease complications
time frame: at 1 year
description: Microalbuminuria, creatinuria; echocardiography for measurement of systolic ventricular ejection fraction (February), PAH research and measurement IT Vmax; respiratory function tests with measurement of DLCO; MRI brain with ARM and Cervical Pre-transplant anomalies; Radio of the pelvis
measure: ferritin dosage
time frame: at month 3
description: Evaluation of iron overload by ferritin
measure: ferritin dosage
time frame: at month 6
description: Evaluation of iron overload by ferritin
measure: MRI iron overload
time frame: at 12 months
description: hepatic and cardiac MRI to assess the iron overload
arm group label: bone marrow transplant
arm group type: Experimental
description: All the included patient will receive an haploidentical bone marrow transplant with the following protocol concerning the conditioning and GvHD prevention
Conditioning
THYMOGLOBULINE : 0.5mg/kg at D-9 and 2 mg/kg at D-8 and D-7
THIOTEPA: 10mg/kg/j at D-7
CYCLOPHOSPHAMIDE (Endoxan®):14.5mg/kg/j at D-6 and D-5
FLUDARABINE (Fludara®): 30mg/m2 per Day from D-6 to D-2
TBI : 2GY : D -1 Graft : Injection at D0 of G-CSF-stimulated bone marrow transplant.
Prophylaxis of GvHD
CYCLOPHOSPHAMIDE (Endoxan®): 50mg/Kg per Day from D+3 to D+4
Sirolimus and MycophénolateMofétil (MMP) from D+5. In the absence of acute GvHD (aGvHD), stop of MMP to D35 and pursuit of sirolimus 1 year after the graft.
intervention type: Biological
intervention name: bone marrow transplant
description: haploidentical bone marrow transplant
arm group label: bone marrow transplant
criteria: 
gender: All
minimum age: 13 Years
maximum age: 40 Years
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: France
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PMID: 25203083
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PMID: 23450875
citation: Bernaudin F, Socie G, Kuentz M, Chevret S, Duval M, Bertrand Y, Vannier JP, Yakouben K, Thuret I, Bordigoni P, Fischer A, Lutz P, Stephan JL, Dhedin N, Plouvier E, Margueritte G, Bories D, Verlhac S, Esperou H, Coic L, Vernant JP, Gluckman E; SFGM-TC. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007 Oct 1;110(7):2749-56. doi: 10.1182/blood-2007-03-079665. Epub 2007 Jul 2.
PMID: 17606762
citation: Kuentz M, Robin M, Dhedin N, Hicheri Y, Peffault de Latour R, Rohrlich P, Bordigoni P, Bruno B, Socie G, Bernaudin F. Is there still a place for myeloablative regimen to transplant young adults with sickle cell disease? Blood. 2011 Oct 20;118(16):4491-2; author reply 4492-3. doi: 10.1182/blood-2011-07-367490. No abstract available.
PMID: 22021455
citation: Angelucci E, Matthes-Martin S, Baronciani D, Bernaudin F, Bonanomi S, Cappellini MD, Dalle JH, Di Bartolomeo P, de Heredia CD, Dickerhoff R, Giardini C, Gluckman E, Hussein AA, Kamani N, Minkov M, Locatelli F, Rocha V, Sedlacek P, Smiers F, Thuret I, Yaniv I, Cavazzana M, Peters C; EBMT Inborn Error and EBMT Paediatric Working Parties. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica. 2014 May;99(5):811-20. doi: 10.3324/haematol.2013.099747.
PMID: 24790059
citation: Hsieh MM, Fitzhugh CD, Weitzel RP, Link ME, Coles WA, Zhao X, Rodgers GP, Powell JD, Tisdale JF. Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA. 2014 Jul 2;312(1):48-56. doi: 10.1001/jama.2014.7192.
PMID: 25058217
citation: Bolanos-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ, Brodsky RA. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood. 2012 Nov 22;120(22):4285-91. doi: 10.1182/blood-2012-07-438408. Epub 2012 Sep 6.
PMID: 22955919
citation: Kamani NR, Walters MC, Carter S, Aquino V, Brochstein JA, Chaudhury S, Eapen M, Freed BM, Grimley M, Levine JE, Logan B, Moore T, Panepinto J, Parikh S, Pulsipher MA, Sande J, Schultz KR, Spellman S, Shenoy S. Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biol Blood Marrow Transplant. 2012 Aug;18(8):1265-72. doi: 10.1016/j.bbmt.2012.01.019. Epub 2012 Feb 16.
PMID: 22343376
citation: Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley TA, Piantadosi S, Kaup M, Ambinder RF, Huff CA, Matsui W, Bolanos-Meade J, Borrello I, Powell JD, Harrington E, Warnock S, Flowers M, Brodsky RA, Sandmaier BM, Storb RF, Jones RJ, Fuchs EJ. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008 Jun;14(6):641-50. doi: 10.1016/j.bbmt.2008.03.005.
PMID: 18489989
citation: McCurdy SR, Kanakry JA, Showel MM, Tsai HL, Bolanos-Meade J, Rosner GL, Kanakry CG, Perica K, Symons HJ, Brodsky RA, Gladstone DE, Huff CA, Pratz KW, Prince GT, Dezern AE, Gojo I, Matsui WH, Borrello I, McDevitt MA, Swinnen LJ, Smith BD, Levis MJ, Ambinder RF, Luznik L, Jones RJ, Fuchs EJ, Kasamon YL. Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood. 2015 May 7;125(19):3024-31. doi: 10.1182/blood-2015-01-623991. Epub 2015 Mar 26.
PMID: 25814532
citation: Bashey A, Zhang X, Sizemore CA, Manion K, Brown S, Holland HK, Morris LE, Solomon SR. T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplantation. J Clin Oncol. 2013 Apr 1;31(10):1310-6. doi: 10.1200/JCO.2012.44.3523. Epub 2013 Feb 19.
PMID: 23423745
citation: Bashey A, Zhang X, Jackson K, Brown S, Ridgeway M, Solh M, Morris LE, Holland HK, Solomon SR. Comparison of Outcomes of Hematopoietic Cell Transplants from T-Replete Haploidentical Donors Using Post-Transplantation Cyclophosphamide with 10 of 10 HLA-A, -B, -C, -DRB1, and -DQB1 Allele-Matched Unrelated Donors and HLA-Identical Sibling Donors: A Multivariable Analysis Including Disease Risk Index. Biol Blood Marrow Transplant. 2016 Jan;22(1):125-33. doi: 10.1016/j.bbmt.2015.09.002. Epub 2015 Sep 7.
PMID: 26359881
citation: Ciurea SO, Mulanovich V, Saliba RM, Bayraktar UD, Jiang Y, Bassett R, Wang SA, Konopleva M, Fernandez-Vina M, Montes N, Bosque D, Chen J, Rondon G, Alatrash G, Alousi A, Bashir Q, Korbling M, Qazilbash M, Parmar S, Shpall E, Nieto Y, Hosing C, Kebriaei P, Khouri I, Popat U, de Lima M, Champlin RE. Improved early outcomes using a T cell replete graft compared with T cell depleted haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2012 Dec;18(12):1835-44. doi: 10.1016/j.bbmt.2012.07.003. Epub 2012 Jul 11.
PMID: 22796535
citation: Raiola AM, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F, Bregante S, Van Lint MT, Geroldi S, Luchetti S, Ballerini F, Miglino M, Varaldo R, Bacigalupo A. Unmanipulated haploidentical bone marrow transplantation and posttransplantation cyclophosphamide for hematologic malignancies after myeloablative conditioning. Biol Blood Marrow Transplant. 2013 Jan;19(1):117-22. doi: 10.1016/j.bbmt.2012.08.014. Epub 2012 Aug 29.
PMID: 22940057
citation: Kanakry CG, Ganguly S, Zahurak M, Bolanos-Meade J, Thoburn C, Perkins B, Fuchs EJ, Jones RJ, Hess AD, Luznik L. Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide. Sci Transl Med. 2013 Nov 13;5(211):211ra157. doi: 10.1126/scitranslmed.3006960.
PMID: 24225944
citation: Ganguly S, Ross DB, Panoskaltsis-Mortari A, Kanakry CG, Blazar BR, Levy RB, Luznik L. Donor CD4+ Foxp3+ regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice. Blood. 2014 Sep 25;124(13):2131-41. doi: 10.1182/blood-2013-10-525873. Epub 2014 Aug 18.
PMID: 25139358
citation: Stem Cell Trialists' Collaborative Group. Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol. 2005 Aug 1;23(22):5074-87. doi: 10.1200/JCO.2005.09.020.
PMID: 16051954
citation: Yang JZ, Zhang JQ, Sun LX. Mechanisms for T cell tolerance induced with granulocyte colony-stimulating factor. Mol Immunol. 2016 Feb;70:56-62. doi: 10.1016/j.molimm.2015.12.006. Epub 2015 Dec 17.
PMID: 26703218
citation: Jun HX, Jun CY, Yu ZX. In vivo induction of T-cell hyporesponsiveness and alteration of immunological cells of bone marrow grafts using granulocyte colony-stimulating factor. Haematologica. 2004 Dec;89(12):1517-24.
PMID: 15590404
citation: Deotare U, Al-Dawsari G, Couban S, Lipton JH. G-CSF-primed bone marrow as a source of stem cells for allografting: revisiting the concept. Bone Marrow Transplant. 2015 Sep;50(9):1150-6. doi: 10.1038/bmt.2015.80. Epub 2015 Apr 27.
PMID: 25915812
citation: Couban S, Messner HA, Andreou P, Egan B, Price S, Tinker L, Meharchand J, Forrest DL, Lipton J. Bone marrow mobilized with granulocyte colony-stimulating factor in related allogeneic transplant recipients: a study of 29 patients. Biol Blood Marrow Transplant. 2000;6(4A):422-7. doi: 10.1016/s1083-8791(00)70033-4.
PMID: 10975510
citation: Isola L, Scigliano E, Fruchtman S. Long-term follow-up after allogeneic granulocyte colony-stimulating factor--primed bone marrow transplantation. Biol Blood Marrow Transplant. 2000;6(4A):428-33. doi: 10.1016/s1083-8791(00)70034-6.
PMID: 10975511
citation: Ji SQ, Chen HR, Wang HX, Yan HM, Pan SP, Xun CQ. Comparison of outcome of allogeneic bone marrow transplantation with and without granulocyte colony-stimulating factor (lenograstim) donor-marrow priming in patients with chronic myelogenous leukemia. Biol Blood Marrow Transplant. 2002;8(5):261-7. doi: 10.1053/bbmt.2002.v8.pm12064363.
PMID: 12064363
citation: Morton J, Hutchins C, Durrant S. Granulocyte-colony-stimulating factor (G-CSF)-primed allogeneic bone marrow: significantly less graft-versus-host disease and comparable engraftment to G-CSF-mobilized peripheral blood stem cells. Blood. 2001 Dec 1;98(12):3186-91. doi: 10.1182/blood.v98.12.3186.
PMID: 11719353
citation: Serody JS, Sparks SD, Lin Y, Capel EJ, Bigelow SH, Kirby SL, Gabriel DA, Wiley JM, Brecher ME, Schell MJ, Folds J, Shea TC. Comparison of granulocyte colony-stimulating factor (G-CSF)--mobilized peripheral blood progenitor cells and G-CSF--stimulated bone marrow as a source of stem cells in HLA-matched sibling transplantation. Biol Blood Marrow Transplant. 2000;6(4A):434-40. doi: 10.1016/s1083-8791(00)70035-8.
PMID: 10975512
responsible party type: Principal Investigator
investigator affiliation: Saint-Louis Hospital, Paris, France
investigator full name: Nathalie Dhédin
investigator title: Principal Investigator
mesh term: Anemia, Sickle Cell