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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 : January 25, 2018
Sponsor:
Collaborators:
Keocyt
ACTIV
Information provided by (Responsible Party):
Nathalie Dhédin, Saint-Louis Hospital, Paris, France

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.

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Biological: bone marrow transplant Phase 2

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Haploidentical Marrow Transplants
Masking: None (Open Label)
Primary Purpose: Other
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
Actual Study Start Date : August 10, 2017
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
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.
Biological: bone marrow transplant
haploidentical bone marrow transplant



Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. haematologic reconstitution [ Time Frame: 2 years ]
    defined as a neutrophil count> 500 / mm3 and platelets> 20000 / mm3, for three consecutive days.

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. hemoglobin electrophoresis [ Time Frame: at 1 month ]
  13. hemoglobin electrophoresis [ Time Frame: at 2 month ]
  14. hemoglobin electrophoresis [ Time Frame: at 3 months ]
  15. hemoglobin electrophoresis [ Time Frame: at 4 months ]
  16. hemoglobin electrophoresis [ Time Frame: at 5 months ]
  17. hemoglobin electrophoresis [ Time Frame: at 6 months ]
  18. hemoglobin electrophoresis [ Time Frame: at 9 months ]
  19. hemoglobin electrophoresis [ Time Frame: at 12 months ]
  20. hemoglobin electrophoresis [ Time Frame: at 24 months ]
  21. occurence of graft versus host disease [ Time Frame: at month 24 ]
    evaluated monthly from M1 to M6, and M9, M12, M24

  22. grade of graft versus host disease [ Time Frame: at month 24 ]
    Incidence and grade of GvHD, toxic deaths and infectious complications and secondary cancer

  23. occurrence of toxic deaths [ Time Frame: at month 24 ]
  24. occurrence of infectious complications [ Time Frame: at month 24 ]
  25. occurrence of secondary cancer [ Time Frame: at month 24 ]
  26. 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.

  27. ECOG score value [ Time Frame: 2 years ]
    Index Trading ECOG complete physical examination with determination of weight

  28. 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

  29. ferritin dosage [ Time Frame: at month 3 ]
    Evaluation of iron overload by ferritin

  30. ferritin dosage [ Time Frame: at month 6 ]
    Evaluation of iron overload by ferritin

  31. MRI iron overload [ Time Frame: at 12 months ]
    hepatic and cardiac MRI to assess the iron overload



Information from the National Library of Medicine

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Ages Eligible for Study:   13 Years to 40 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03240731


Contacts
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

Locations
France
CHU Henri-Mondor Recruiting
Créteil, France, 94000
Contact: Sébastien Maury         
intercommunal hospital of Créteil Recruiting
Créteil, France, 94000
Contact: Corinne Pondarre         
Contact: Françoise Bernaudin         
CHU La Timone Not yet recruiting
Marseille, France
Contact: Claire Galambrun         
Hospital Necker Recruiting
Paris, France
Contact: Felipe Suarez         
Hospital Robert-Debré Recruiting
Paris, France
Contact: Jean-Hugue Dalle         
Saint-Louis hospital Recruiting
Paris, France
Contact: Nathalie Dhédin, MD, PhD         
Contact: Gérard Socie         
CHU Strasbourg Recruiting
Strasbourg, France
Contact: Catherine Paillard         
Sponsors and Collaborators
Centre Hospitalier Intercommunal Creteil
Keocyt
ACTIV

Publications:

Responsible Party: Nathalie Dhédin, Principal Investigator, Saint-Louis Hospital, Paris, France
ClinicalTrials.gov Identifier: NCT03240731     History of Changes
Other Study ID Numbers: DREPHAPLO
First Posted: August 7, 2017    Key Record Dates
Last Update Posted: January 25, 2018
Last Verified: August 2017

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Nathalie Dhédin, Saint-Louis Hospital, Paris, France:
sickle cell disease
haploidentical
graft
marrow

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Cyclophosphamide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists