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HLA Haploidentical Bone Marrow Transplant in Patients With Severe Sickle Cell Disease (DREPHAPLO)

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ClinicalTrials.gov Identifier: NCT03240731
Recruitment Status : Recruiting
First Posted : August 7, 2017
Last Update Posted : February 6, 2019
Sponsor:
Collaborators:
Keocyt
ACTIV
Information provided by (Responsible Party):
Nathalie Dhédin, Saint-Louis Hospital, Paris, France

Tracking Information
First Submitted Date  ICMJE July 31, 2017
First Posted Date  ICMJE August 7, 2017
Last Update Posted Date February 6, 2019
Actual Study Start Date  ICMJE August 10, 2017
Estimated Primary Completion Date September 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 2, 2017)
Survival rate [ Time Frame: 2 years ]
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
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03240731 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 2, 2017)
  • Survival rate [ Time Frame: 1 year ]
    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
  • haematologic reconstitution [ Time Frame: 2 years ]
    defined as a neutrophil count> 500 / mm3 and platelets> 20000 / mm3, for three consecutive days.
  • Chimerism [ Time Frame: at month 1 ]
    Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
  • Chimerism [ Time Frame: at month 2 ]
    Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
  • Chimerism [ Time Frame: at month 3 ]
    Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
  • Chimerism [ Time Frame: at month 4 ]
    Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
  • Chimerism [ Time Frame: at month 5 ]
    Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
  • Chimerism [ Time Frame: at month 6 ]
    Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
  • Chimerism [ Time Frame: at month 9 ]
    Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
  • Chimerism [ Time Frame: at month 12 ]
    Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
  • Chimerism [ Time Frame: at month 24 ]
    Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers
  • hemoglobin electrophoresis [ Time Frame: at 1 month ]
  • hemoglobin electrophoresis [ Time Frame: at 2 month ]
  • hemoglobin electrophoresis [ Time Frame: at 3 months ]
  • hemoglobin electrophoresis [ Time Frame: at 4 months ]
  • hemoglobin electrophoresis [ Time Frame: at 5 months ]
  • hemoglobin electrophoresis [ Time Frame: at 6 months ]
  • hemoglobin electrophoresis [ Time Frame: at 9 months ]
  • hemoglobin electrophoresis [ Time Frame: at 12 months ]
  • hemoglobin electrophoresis [ Time Frame: at 24 months ]
  • occurence of graft versus host disease [ Time Frame: at month 24 ]
    evaluated monthly from M1 to M6, and M9, M12, M24
  • grade of graft versus host disease [ Time Frame: at month 24 ]
    Incidence and grade of GvHD, toxic deaths and infectious complications and secondary cancer
  • occurrence of toxic deaths [ Time Frame: at month 24 ]
  • occurrence of infectious complications [ Time Frame: at month 24 ]
  • occurrence of secondary cancer [ Time Frame: at month 24 ]
  • Lymphocyte immunophenotyping [ Time Frame: 2 years ]
    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.
  • ECOG score value [ Time Frame: 2 years ]
    Index Trading ECOG complete physical examination with determination of weight
  • Assessment of sickle cell disease complications [ Time Frame: at 1 year ]
    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
  • ferritin dosage [ Time Frame: at month 3 ]
    Evaluation of iron overload by ferritin
  • ferritin dosage [ Time Frame: at month 6 ]
    Evaluation of iron overload by ferritin
  • MRI iron overload [ Time Frame: at 12 months ]
    hepatic and cardiac MRI to assess the iron overload
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE HLA Haploidentical Bone Marrow Transplant in Patients With Severe Sickle Cell Disease
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Intervention Model Description:
Haploidentical Marrow Transplants
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Sickle Cell Disease
Intervention  ICMJE Biological: bone marrow transplant
haploidentical bone marrow transplant
Study Arms  ICMJE Experimental: bone marrow transplant

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: Biological: bone marrow transplant
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 2, 2017)
15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2020
Estimated Primary Completion Date September 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria recipient:

  • Age: 13 years-40 years
  • Severe Sickle cell with at least one of the following criteria:

    • Stenosing vasculopathy with abnormal MRA despite prolonged transfusion program
    • PAH confirmed by right catheterization with mPAP> 25mmHg
    • Systolic ejection fraction <55% and tricuspid regurgitation speed> 2.5m /s at distance from an acute episode
    • No possibility of blood transfusion or very complicated blood transfusion
    • Report albumin / creatinine> 30 mg / mmol, confirmed 3 times, away at distance from acute episode and persistent despite hydroxyurea or IEC
    • GFR <80ml / min /1.73m2 (CKD-Epi without ethnic criterion)
    • Previous history of acute liver sequestration with liver failure
    • Acute chest syndrome or vaso-occlusive crises under hydroxyurea
    • Complications of sickle cell transfusion imposing an exchange program with no possible withdrawal beyond a period of one year
  • Not having geno-identical donor, but a haploidentical major donor (parent, sibling, adult child, or HbAA AS)
  • Having red and understood the information letter and signed the informed consent
  • Patients affiliated to a social security system (Social Security or Universal Medical Coverage)

Exclusion Criteria recipient:

  • Patient with a geno-identical donor
  • Performans status: ECOG> 1
  • lung disease: FEV1 and FVC <50% predicted,
  • score of PAH NYHA≥2
  • Liver disease with bilirubin> 50 .mu.mol / L
  • heart failure defined by NYHA≥3 score ejection fraction <45% or shortening fraction <24%
  • anti HLA alloimmunization against the donor or against red cell antigens of the donor
  • Serology or HIV viral load positively
  • Patients who for family, social or geographical reasons, do not wish to be regularly monitored in consultation
  • severe uncontrolled infection at the time of inclusion or graft
  • pregnant woman (positive beta HCG) or during lactation
  • incapable adult patient, trust, guardianship, or safeguard justice

Inclusion criteria donor

  • Age> 18 years and <60 years
  • Viral serologic economy allows the graft
  • No contraindication for general anesthesia
  • No contraindication the administration of G-CSF (the existence of sickle cell trait is not a contraindication)
  • Lack antigens HLA recognized by the recipient antibody
  • Hemoglobin S <50%
  • When several donors are compatible: choose according to the ABO recipient: prefer ABO compatibility and major incompatibility and minor incompatibility, and finally major and minor incompatibility.
  • Signature of informed consent
  • Non-inclusion criteria donors: β HCG positive or known pregnancy
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 13 Years to 40 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Nathalie Dhedin, MD, PhD +33-1-4238 51 27 nathalie.dhedin@sls.aphp.fr
Contact: Camille Jung, MD, PhD +33-1-45175433 camille.jung@chicreteil.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03240731
Other Study ID Numbers  ICMJE DREPHAPLO
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Nathalie Dhédin, Saint-Louis Hospital, Paris, France
Study Sponsor  ICMJE Centre Hospitalier Intercommunal Creteil
Collaborators  ICMJE
  • Keocyt
  • ACTIV
Investigators  ICMJE Not Provided
PRS Account Centre Hospitalier Intercommunal Creteil
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP