Natural History Study of SCID Disorders

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Prospective Natural History Study of Diagnosis, Treatment and Outcomes of Children With SCID Disorders (RDCRN PIDTC-6901)

Conditions
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Severe Combined Immunodeficiency (SCID), Leaky SCID, Omenn Syndrome, Reticular Dysgenesis, ADA SCID, XSCID

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Stratum C: Subjects who meet the following criteria and the intention is to treat with therapy other than allogeneic HCT, primarily PEG-ADA ERT or gene therapy with autologous modified (gene transduced) cells, are eligible for enrollment into Stratum C: ADA Deficient SCID with intention to treat with PEG-ADA ERT ADA Deficient SCID with intention to treat with gene therapy X-linked SCID with intention to treat with gene therapy Any SCID patient previously treated with a thymus transplant (includes intention to treat with HCT, as well as PEG-ADA ERT or gene therapy) Any SCID patient who received therapy for SCID deemed non-standard or investigational, including in utero procedures. Exclusion Criteria: -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.
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 |
| --- | --- |
| Stratum A: Typical SCID +HCT<br>Stratum A: Typical Severe Combined Immunodeficiency (SCID) treated with HCT therapy. Participants with typical (formerly referred to as classic) SCID + allogeneic hematopoietic stem cell transplantation (HCT) therapy according to standard of care, per local protocol. | |
| Stratum B: Atypical SCID +HCT<br>Stratum B: Atypical Severe Combined Immunodeficiency (SCID) treated with HCT therapy. Participants with leaky SCID, Omenn syndrome, or Reticular Dysgenesis (RS) + allogeneic hematopoietic stem cell transplantation (HCT) therapy according to standard of care, per local protocol. | |
| Stratum C:SCID +Non-HCT<br>Stratum C: Severe Combined Immunodeficiency (SCID) who receive alternative therapy per standard of care, non-standard care and/or investigational. This stratum includes: Adenosine Deaminase-Deficient SCID (ADA Deficient SCID) with intention to treat with Polyethylene Glycol -Adenosine Deaminase Enzyme Replacement Therapy (PEG-ADA ERT) ADA Deficient SCID with intention to treat with gene therapy X-linked SCID (XSCID) with intention to treat with gene therapy Any individual with SCID previously treated with a thymus transplant (includes intention to treat with HCT, as well as PEG-ADA ERT or gene therapy) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) at 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. | Month 6 Post HCT | 
| Overall Survival (OS) at 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. | Year 2 Post HCT | 
| Overall Survival (OS) at 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. | Year 5 Post HCT | 
| Overall Survival (OS) at 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. | Year 8 Post HCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| T Cell Reconstitution by Stratum-Month 6, Year 2, Year 5 and Year 8 Post-SCID Treatment | A measure of immune reconstitution defined by the presence of three out of four of: Lymphocyte proliferation to PHA ≥50% of lower limit of normal control Total CD3+ > 1000 / microliter Total CD4+ > 500 / microliter Total CD4+ CD45RA+ > 200 / microliter AND, for participants who received allogeneic HCT: -Donor T cell chimerism ≥80% | From SCID Treatment (HCT, ERT or GT) to Month 6, Year 2, Year 5 and Year 8 Post-SCID Treatment | 
| B Cell Reconstitution by Stratum-Month 6, Year 2, Year 5 and Year 8 Post-SCID Treatment | A measure of immune reconstitution defined by: -Intravenous Immunoglobulin (IVIG) independence and at least three of the following: Normal IgA and IgM levels for age Normal IgG levels for age, independent of supplemental gammaglobulin Isohemagglutinins ≥1:8 Specific antibody production while off IVIG | 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 | Whole-blood engraftment and engraftment in T-, B-, or Natural Killer (NK)-cell subsets will be assessed. For whole blood and subsets*, the following engraftment criteria will be used: < 5% donor = autologous reconstitution 5-80% donor = mixed chimerism ≥ 80% donor = full chimerism Subsets: CD3 CD19 CD14 and/or CD15 (myeloid cells) CD3- CD56+ NK cells Outcome analysis restricted to participants with hematopoietic (stem) cell transplantation (HCT) intervention. | From HCT to Month 6, Year 2, Year 5 and Year 8 Post-HCT | 
| Time to Resolution of Infections Diagnosed Prior to HCT | Time to resolution of any pre-HCT infections-bacterial, viral or fungal. Participants who are alive without resolving their pre-HCT infections will be considered censored at last contact. Resolution of pre-existing infection defined by: Participant being clinically well, Participant off treatment for infection(s), and/or Negative culture/PCR assay. Outcome analysis restricted to participants with pre-hematopoietic (stem) cell transplantation (HCT) opportunistic infections. | Through study completion, up to 8 years post-HCT | 
| Incidence of New Infections Post-HCT | The occurrence of new documented bacterial, viral, or fungal infections-by site of disease, organism, date of onset, and resolution- post-HCT. Participants who are alive without infection will be considered censored at last contact. Outcome analysis restricted to participants with hematopoietic (stem) cell transplantation (HCT). | From HCT to Day 100, Month 6, Year 1, Year 2, Year 5, and Year 8 post-HCT | 
| Proportion of Participants Achieving Normal Nutritional Status Post-HCT | Normal nutrition status defined by: Absence of chronic diarrhea and/or No longer requiring supplemental nutrition (i.e., tube feeding or TPN). TPN: total parenteral nutrition Outcome analysis restricted to participants with hematopoietic (stem) cell transplantation (HCT) intervention. | Baseline (Pre-HCT) to Year 1, Year 2, Year 5 and Year 8 Post-HCT | 
| Longitudinal Analysis: Growth Percentile in Body Height | Participant's height will be superimposed against gender specific standard growth charts. | Baseline (Pre-HCT), Year 1, Year 2, Year 5 and Year 8 Post-HCT | 
| Longitudinal Analysis: Growth Percentile in Body Weight | Participant's weight will be superimposed against gender specific standard growth charts. | Baseline (Pre-HCT), Year 1, Year 2, Year 5 and Year 8 Post-HCT | 
| Incidence of Acute Graft Versus Host Disease (GVHD) Post-HCT | Occurrence of acute GVHD. Any skin, gastrointestinal or liver abnormalities fulfilling the consensus criteria of Grades II-IV acute GVHD or grades III-IV acute GVHD are considered events. Participants alive without acute GVHD will be censored at the time of last follow-up. Outcome analysis restricted to participants with hematopoietic (stem) cell transplantation (HCT) intervention. | From HCT to Day 100 and Month 6 post-HCT | 
| Incidence of Chronic Graft Versus Host Disease (GVHD) Post-HCT | Occurrence of chronic GVHD in any organ system fulfilling the criteria of limited or extensive chronic GVHD. Participants alive without chronic GVHD will be censored at time of last follow-up. Outcome analysis restricted to participants with hematopoietic (stem) cell transplantation (HCT). | From HCT to Month 6, 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 | Occurrence of autoimmunity requiring treatment with immunosuppression or other therapy. Participants alive without autoimmunity will be censored at time of last follow-up. Date of onset and type of treatment will be collected on: Autoimmune hypothyroidism Autoimmune cytopenia (hemolytic anemia, thrombocytopenia, neutropenia) Arthritis Myositis Nephritis Bronchiolitis obliterans or other pulmonary autoimmune disease Vitiligo Alopecia Inflammatory bowel disease Neurodegeneration Vasculitis | From SCID Treatment (HCT, ERT or GT) to Month 6, Year 2, 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) | Infant development as measured by Bayley's scales for infant development 3rd edition (BSID-III-R, Bayley, 2006).] The BSID III-R is a standardized developmental exam that is normalized to the age of the child in months. The mean adjusted score is 100 with a standard deviation of 15 (higher being better). Evaluation conducted as per standard of care in participants ≤30 months of age. | 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 Vineland Adaptive Behavior Scales, Second Edition (Vineland II) | The Vineland II measures the personal and social skills of individuals from birth through adulthood. Since adaptive behavior refers to an individual's typical performance of the day-to-day activities required for personal and social sufficiency, these scales assess what a person actually does, rather than what he or she is able to do. Summary: The Vineland II is a measure of adaptive behavior in children, adolescents and adults. It yields an overall standard score (Adaptive Behavior Composite, ABC) and age standard scores in four domains: Communication, Daily Living Skills, Motor Skills, and Maladaptive Behaviour Index. ABC scores have a mean of 100 and a standard deviation of 15 (range = 20 to 160). Higher scores suggest a higher level of adaptive functioning. A rise in standard scores from Baseline indicates improvement. Evaluation as per standard of care. | 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) | Cognitive ability assessed using the WPPSI III. The WPPSI-III has been developed and standardized for children ages 2 years, 6 months through 7 years, 3 months of age. The WPPSI-III yields a Verbal Score, a Performance Score, a General Language Score, and a Full Scale Score. These scores have a mean of 100 and a standard deviation of 15. The range of possible values is 50 (worst value) to 150 (best value). Evaluation as per standard of care. | Baseline (Pre-SCID Treatment-HCT, ERT or GT),Year 1, Year 2, Year 4, Year 5 and Year 8 Post-SCID Treatment | 
| Neurocognitive Assessment by Stratum Using the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) | The WISC-IV is designed for children 6 years 0 months to 16 years 11 months. The Full Scale IQ, ranges from 45 to 155 with a mean of 100 and standard deviation of 15. Higher scores indicate stronger cognitive function. Scores between 90 and 110 are considered to be within the range of average IQ. Evaluation in accordance with standard of care, participant ages 6 years and above. | 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 | Occurrence of health event(s) classified as an HCT treatment complication, including but not limited to: Veno-occlusive disease Thrombotic thrombocytopenic purpura Bronchiolitis obliterans / chronic lung disease Seizures Hypertension Outcome analysis restricted to participants with hematopoietic (stem) cell transplantation (HCT) intervention. | From HCT to Month 6, Year 1,Year 2, Year 5 and Year 8 Post-HCT | 
| Comparison of Quality of Life (QOL) By Stratum Prior to and After SCID Treatment: Scores for Pediatric Quality of Life Questionnaire (Peds-QL) | The Peds-QL is a generic Health-Related Quality of Life (HR QoL) instrument designed specifically for a pediatric population. It captures the following domains: general health/activities, feelings/emotional, social functioning, school functioning. Higher scores indicate better quality of life (QOL) for all domains of the Peds-QL. This modular instrument uses a 5-point scale: from 0 (never) to 4 (almost always). Items are reversed scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. 4 dimensions (physical, emotional, social, & school functioning) are scored. | Baseline (Pre-SCID Treatment-HCT, ERT or GT) to Year 1, Year 2, Year 4, Year 5 and Year 8 Post-SCID Treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Severe Combined Immunodeficiency (SCID), natural history study, SCID treatment