Multi-center Clinical Study of Cord Blood Stem Cell Transplantation for SCID

Study Overview
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Brief Summary
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Severe combined immunodeficiency (SCID) is a rare disease caused by a group of genetic disorders that leads to early death from recurrent infections in affected children.The only curative therapy for SCID is allogeneic hematopoietic stem cell transplantation.Unrelated umbilical cord blood(UCB) is increasingly used as an alternative to bone marrow.

Detailed Description
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Severe combined immunodeficiency (SCID) is a rare disease caused by a group of genetic disorders that leads to early death from recurrent infections in affected children.The only curative therapy for SCID is allogeneic hematopoietic stem cell transplantation.Unrelated umbilical cord blood(UCB) is increasingly used as an alternative to bone marrow.The development of NBS in Europe and America has enabled more SCID patients to be diagnosed before symptoms appear, and to enter the normative assessment and intervention procedures as soon as possible. In China SCID has not been included in the NBS program,and there are few units that can diagnose SCID.Patients often delay diagnosis and miss the best period of transplantation. Department of Hematology, Children's Hospital of Fudan University, has used UCBT for the treatment of SCID patients with reduced intensity conditioning(RIC)since 2014.6 of 8 cases were treated with disease-free survival. The encouraging efficacy of these patients suggests that RIC of UCBT may be an effective treatment for SCID patients to urgently hematopoietic stem cell transplantation. The aim of this study is to investigate the efficacy of UCBT in the treatment of SCID, including engraftment rate, disease-free survival rate,overall survival rate and immune reconstitution, and to evaluate transplant-related mortality and complications. All the selected cases are diagnosed as severe combined immunodeficiency disease by immunological function and gene detection. These patients have no matched sibling donors. Their organs function should be normal. The guardian of the patient has the desire and requirement for UCBT and signs the informed consent before treatment. Cord blood stem cell selection:HLA high-resolution detection of patients before transplantation, searching through cord blood stem cell bank, selecting cord blood stem cells that meet the following criteria: HLA-A, B, C, DRB1 high-resolution (genotype) > 6/8matching,total number of nuclear cells >5x10^7/kg.Conditioning:busulfan+ cyclophosphamide.GVHD prevention: tacrolimus (FK506) or cyclosporine A. Infection prevention: Micafungin/caspofungin before engraftment, voriconazole after engraftment to prevent fungi. Ganciclovir is used from the beginning of conditioning to the infusion of cord blood stem cells, and acyclovir is used to prevent virus infection. SMZ prevents Pneumocystis carinii infection after engraftment until half a year after the withdrawal of immunosuppressive agents. This is a multicenter prospective observational study. Procedure/Surgery: Cord Blood Stem Cell Transplantation Unrelated cord blood stem cell selection: HLA high-resolution detection is performed before transplantation. High-resolution (genotype) matching of HLA-A, B, C and DRB1 was selected. The total number of nuclear cells is more than 5*107/kg. Reduced intensity conditioning : Busulphan 3.2mg/kg per day in divided doses for 3 days(total dose 9.6 mg/kg) and cyclophosphamide 50 mg/kg for 2 days (total dose 100 mg/kg). GVHD prevention: tacrolimus (FK506) 0.1 mg/kg/day, started 4 days before transplantation, is taken orally twice, and the blood concentration is monitored to maintain the concentration at 5-10 ng/ml. If the patient does not have a GVHD transplant +100 days after the slow reduction, until the transplant 6 months after the withdrawal. Infection prevention: Micafungin/caspofungin before engraftment, voriconazole after engraftment to prevent fungi. Ganciclovir is used from the beginning of pretreatment to the beginning of reinfusion, and acyclovir is used to prevent virus infection until immunosuppressive agents are discontinued after reinfusion. SMZ prevents Pneumocystis carinii infection after engraftment.

Official Title
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Multi-center Clinical Study of Cord Blood Stem Cell Transplantation for Severe Combined Immunodeficiency Disease

Conditions
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Severe Combined Immunodeficiency Disease

Intervention / Treatment
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* Procedure: cord blood stem cell transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients were diagnosed as severe combined immunodeficiency disease by immunological function and genetic diagnosis center. Patients have no HLA-matched related donor. Each organ functions normally and conforms the following inspection criteria: Liver function ALT, AST ≤ 10 times the upper limit of normal value, TBIL ≤ 5 times the upper limit of normal value. Renal function BUN, Cr ≤ 1.25 times the upper limit of normal value. ECG, cardiac examination normal Exclusion Criteria: Patients have any contraindications to hematopoietic stem cell transplantation. Patients have other serious diseases, such as serious damage to vital organ function: respiratory failure, cardiac insufficiency, decompensated liver dysfunction, renal insufficiency, uncontrollable infection, etc. The patient is undergoing other drug clinical research. At the same time suffering from other serious acute or chronic physical or mental illness, or laboratory abnormalities, may affect patient safety and compliance, affecting informed consent, research participation, follow-up or interpretation of results.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| UCBT-SCID-Case<br>SCID patients who underwent cord blood stem cell transplantation.The only curative therapy for SCID is allogeneic hematopoietic stem cell transplantation. | Procedure: cord blood stem cell transplantation<br>* Unrelated cord blood stem cell selection； Reduced intensity conditioning； GVHD prevention； Infection prevention.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival rate | Overall survival is defined as the survival status of patients by the end of 3 years after the transplanting, coded as 1 for dead and 0 for survive. | 3 years after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival rate | Disease free survival is defined as the survival status of patients by the end of the third year after transplantation. Disease free survival is defined as survive without conditions including engraftment failure and death caused by any reasons. The variable is coded as 0 for disease free survive, and 1 for all conditions other than the defined status of 0. | 3 years after transplantation | 
| Successful engraftment | The event of successful engraftment is defined as Neutrophil count ≥ 0.5×10^9/L for continuous 3 days and platelet count ≥ 20×10^9/L for continuous 7 days without transfusion. It is coded as 1. | 3 years after transplantation | 
| Immune reconstitution | Immune reconstitution is including T-cell and B-cell reconstitution.The variable would be coded as 1 if any of these two cells had been reconstituted while 0 for none. T-cell reconstitution is defined as meeting these criteria: CD3+ cell count > 1000 per cubic millimeter, and CD4+ cell count > 500 per cubic millimeter. B-cell reconstitution is defined as independence from Ig-replacement therapy. | 3 years after transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cord blood stem cell transplantation, severe combined immunodeficiency disease, primary immunodeficiency