A Prospective Natural History Study of Diagnosis, Treatment and Outcomes of Children With SCID Disorders (RDCRN PIDTC-6901)
试验速览
- 阶段
- 不适用
- 状态
- Enrolling By Invitation
- 入组人数
- 690
- 试验地点
- 44
- 主要终点
- Overall Survival (OS) at Month 6 Post HCT
研究概览
简要总结
This study is a prospective evaluation of children with Severe Combined Immune Deficiency (SCID) who are treated under a variety of protocols used by participating institutions. In order to determine the patient, recipient and transplant-related variables that are most important in determining outcome, study investigators will uniformly collect pre-, post- and peri-transplant (or other treatment) information on all children enrolled into this study.
Children will be divided into three strata:
- Stratum A: Typical SCID with virtual absence of autologous T cells and poor T cell function
- Stratum B: Atypical SCID (leaky SCID, Omenn syndrome and reticular dysgenesis with limited T cell diversity or number and reduced function), and
- Stratum C: ADA deficient SCID and XSCID patients receiving alternative therapy including PEG-ADA ERT or gene therapy.
Each Group/Cohort Stratum will be analyzed separately.
详细描述
This study follows participants with SCID prospectively, meaning the study enrolls participants where there is a plan to receive a blood and marrow transplant, enzyme therapy, or gene therapy in the future. Participants are then followed according to a schedule set out by the study protocol after the procedure. There are no experimental therapies on this study.
The goal of this study is to learn more about: (1) outcomes from the treatment of SCID in the modern era of medicine (2) what factors lead to the best long-term outcomes, such as best donor, conditioning regimen, timing of transplant, etc., and (3) what impact newborn screening and the early diagnosis of SCID has had on the long-term outcomes following BMT or gene therapy. Information is also being gathered on how and when the immune system recovers after bone marrow transplant (BMT), quality of life for long-term survivors, and about whether children develop normally after treatment.
This natural history study is the largest coordinated prospective study of participants with SCID ever performed. Information that investigators will learn, both now and in the future, will help doctors and other health professionals to better treat children with SCID.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Stratum A: Typical SCID (formerly referred to as Classic SCID)- -Subjects who meet the following inclusion criteria and the intention is to treat with allogeneic hematopoietic cell transplant (HCT) are eligible for enrollment into Stratum A (Typical SCID) of the study:
- •Absence or very low number of T cells (CD3 T cells <300/microliter) AND
- •No or very low T cell function (<10% of lower limit of normal) as measured by response to phytohemagglutinin (PHA) OR
- •T cells of maternal origin present.
- •Stratum B: Leaky SCID, Omenn Syndrome, Reticular Dysgenesis-
- •Subjects who meet the following criteria and the intention is to treat with HCT are eligible for enrollment into Stratum B:
- •Leaky SCID:
- •Maternal lymphocytes tested for and not detected AND
- •Either one or both of the following (a,b) :
- •a.) <50% of lower limit of normal T cell function as measured by response to PHA, OR response to anti-CD3/CD28 antibody
- •b.) Absent or <30% of lower limit of normal proliferative responses to candida and tetanus toxoid antigens
- •AND at least two of the following (a through e):
- •a.) Reduced number of CD3 T cells
- •age ≤2 years: <1500/microliter
- •age >2 years and ≤4 years: <800/microliter
- •age >4 years: <600/microliter
- •b.) ≥80% of CD3+ or CD4+ T cells that are CD45RO+
- •AND/OR >80% of CD3+ or CD4+ T cells are CD62L negative
- •AND/OR >50% of CD3+ or CD4+T cells express HLA-DR (at <4 years of age)
- •AND/OR are oligoclonal T cells
- •c.) Hypomorphic mutation in IL2RG in a male, or homozygous hypomorphic mutation or compound heterozygosity with ≥1 hypomorphic mutation in an autosomal SCID-causing gene
- •d.) Low T Cell Receptor Excision Circles (TRECs) and/or the percentage of CD4+/45RA+/CD31+ or CD4+/45RA+/CD62L+ cells is below the lower limit of normal.
- •e.) Functional testing in vitro supporting impaired, but not absent, activity of the mutant protein, AND
- •Does not meet criteria for Omenn Syndrome.
- •Omenn Syndrome:
- •Generalized skin rash
- •Maternal lymphocytes tested for and not detected;
- •-Note: If maternal engraftment was not assessed and ruled out, the subject is not eligible as Omenn Syndrome.
- •≥80% of CD3+ or CD4+ T cells are CD45RO+ AND/OR
- •80% of CD3+ or CD4+T cells are CD62L negative AND/OR
- •50% of CD3+ or CD4+ T cells express HLA-DR (at <2 years of age);
- •Absent or low (< 30% lower limit of normal) T cell proliferation response to antigens (Candida, tetanus) to which the subject has been exposed
- •NOTE: If proliferation to antigen was not performed, but at least 4 of the following 9 supportive criteria, at least one of which must be among those marked with an asterisk (*) below are present, the subject is eligible as Omenn Syndrome:
- •Hepatomegaly
- •Splenomegaly
- •Lymphadenopathy
- •Elevated IgE
- •Elevated absolute eosinophil count
- •*Oligoclonal T cells measured by CDR3 length or flow cytometry
- •*Proliferation to PHA is reduced <50% of lower limit of normal or SI <30
- •*Hypomorphic mutation in a SCID causing gene
- •Low TRECS and/or the percentage of CD4+/45RA+/CD31+ or CD4+/45RA+/CD62L+ cells is below the lower limit of normal.
- •Reticular Dysgenesis:
- •Absence or very low number of T cells (CD3 <300/µL
- •No or very low (<10% lower limit of normal) T cell response to PHA
- •Severe neutropenia (absolute neutrophil count < 200 /µL) AND
- •≥2 of the following (a,b,c):
- •a.) Sensori-neural deafness
- •b.) Deficiency of marrow granulopoiesis on bone marrow examination
- •c.) A pathogenic mutation in the adenylate kinase 2 (AK2) gene identified.
- 另有 6 项未显示
排除标准
- •Subjects who meet any of the following exclusion criteria are disqualified from enrollment in Strata A, B, or C of the study:
- •Presence of an Human Immunodeficiency Virus (HIV) infection (by PCR) or other cause of secondary immunodeficiency
- •Presence of DiGeorge syndrome
- •MHC Class I and MHC Class II antigen deficiency, and
- •Metabolic conditions that imitate SCID or related disorders such as folate transporter deficiency, severe zinc deficiency or transcobalamin deficiency.
结局指标
主要结局
Overall Survival (OS) at Month 6 Post HCT
时间窗: Month 6 Post HCT
Assess the overall survival (OS) for participants after hematopoietic stem cell transplantation (HCT) for treatment of Severe Combined Immunodeficiency (SCID). The time to this event is the time from HCT to death or last follow-up (whichever occurs first). All participants will be followed for a minimum of 6 months from HCT. Overall survival will be estimated at 6 months.
Overall Survival (OS) at Year 2 Post HCT
时间窗: Year 2 Post HCT
Assess the overall survival (OS) for participants after hematopoietic stem cell transplantation (HCT) for treatment of Severe Combined Immunodeficiency (SCID). The time to this event is the time from HCT to death or last follow-up (whichever occurs first). All participants will be followed for a minimum of 6 months from HCT. Overall survival will be estimated at 2 years.
Overall Survival (OS) at Year 8 Post HCT
时间窗: Year 8 Post HCT
Assess the overall survival (OS) for participants after hematopoietic stem cell transplantation (HCT) for treatment of Severe Combined Immunodeficiency (SCID). The time to this event is the time from HCT to death or last follow-up (whichever occurs first). All participants will be followed for a minimum of 6 months from HCT. Overall survival will be estimated at 8 years.
Overall Survival (OS) at Year 5 Post HCT
时间窗: Year 5 Post HCT
Assess the overall survival (OS) for participants after hematopoietic stem cell transplantation (HCT) for treatment of Severe Combined Immunodeficiency (SCID). The time to this event is the time from HCT to death or last follow-up (whichever occurs first). All participants will be followed for a minimum of 6 months from HCT. Overall survival will be estimated at 5 years.
次要结局
- T Cell Reconstitution by Stratum-Month 6, Year 2, Year 5 and Year 8 Post-SCID Treatment(From SCID Treatment (HCT, ERT or GT) to Month 6, Year 2, Year 5 and Year 8 Post-SCID Treatment)
- Engraftment at Day 100, Month 6, Year 2, Year 5 and Year 8 Post-HCT(From HCT to Month 6, Year 2, Year 5 and Year 8 Post-HCT)
- Longitudinal Analysis: Growth Percentile in Body Height(Baseline (Pre-HCT), Year 1, Year 2, Year 5 and Year 8 Post-HCT)
- Incidence of Autoimmunity Requiring Treatment by Stratum- Month 6, Year 2, Year 5 and Year 8 Post-SCID Treatment(From SCID Treatment (HCT, ERT or GT) to Month 6, Year 2, Year 5 and Year 8 Post-SCID Treatment)
- Neurocognitive Assessment by Stratum Using the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV)(Baseline (Pre-SCID Treatment-HCT, ERT or GT),Year 1, Year 2, Year 4, Year 5 and Year 8 Post-SCID Treatment)
- Incidence of Complications of HCT Requiring Treatment(From HCT to Month 6, Year 1,Year 2, Year 5 and Year 8 Post-HCT)
- B Cell Reconstitution by Stratum-Month 6, Year 2, Year 5 and Year 8 Post-SCID Treatment(From SCID Treatment (HCT, ERT or GT) to Month 6, Year 2, Year 5 and Year 8 Post-SCID Treatment)
- Time to Resolution of Infections Diagnosed Prior to HCT(Through study completion, up to 8 years post-HCT)
- Incidence of Chronic Graft Versus Host Disease (GVHD) Post-HCT(From HCT to Month 6, Year 1,Year 2, Year 5 and Year 8 Post-HCT)
- Incidence of New Infections Post-HCT(From HCT to Day 100, Month 6, Year 1, Year 2, Year 5, and Year 8 post-HCT)
- Longitudinal Analysis: Growth Percentile in Body Weight(Baseline (Pre-HCT), Year 1, Year 2, Year 5 and Year 8 Post-HCT)
- Incidence of Acute Graft Versus Host Disease (GVHD) Post-HCT(From HCT to Day 100 and Month 6 post-HCT)
- Proportion of Participants Achieving Normal Nutritional Status Post-HCT(Baseline (Pre-HCT) to Year 1, Year 2, Year 5 and Year 8 Post-HCT)
- Neurocognitive Development By Stratum Measured by Vineland Adaptive Behavior Scales, Second Edition (Vineland II)(Baseline (Pre-SCID Treatment-HCT, ERT or GT),Year 1, Year 2, Year 4, Year 5 and Year 8 Post-SCID Treatment)
- Neurocognitive Development By Stratum Measured by Wechsler Preschool and Primary Intelligence Scale of Intelligence, Third Edition (WPPSI III)(Baseline (Pre-SCID Treatment-HCT, ERT or GT),Year 1, Year 2, Year 4, Year 5 and Year 8 Post-SCID Treatment)
- Infant Neurocognitive Development By Stratum Measured by Bayley's Scales for Infant Development 3rd edition (BSID-III-R)(Baseline (Pre-SCID Treatment-HCT, ERT or GT),Year 1, Year 2, Year 4, Year 5 and Year 8 Post-SCID Treatment)
- Comparison of Quality of Life (QOL) By Stratum Prior to and After SCID Treatment: Scores for Pediatric Quality of Life Questionnaire (Peds-QL)(Baseline (Pre-SCID Treatment-HCT, ERT or GT) to Year 1, Year 2, Year 4, Year 5 and Year 8 Post-SCID Treatment)