Natural History Study of SCID Disorders

Официальное название

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

Обзор

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.

Подробное описание

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.

Первичные конечные точки

• Overall Survival (OS) at Month 6 Post HCT [Срок оценки: Month 6 Post HCT]
• Overall Survival (OS) at Year 2 Post HCT [Срок оценки: Year 2 Post HCT]
• Overall Survival (OS) at Year 5 Post HCT [Срок оценки: Year 5 Post HCT]
• Overall Survival (OS) at Year 8 Post HCT [Срок оценки: Year 8 Post HCT]

Вторичные конечные точки (12)

• T Cell Reconstitution by Stratum-Month 6, Year 2, Year 5 and Year 8 Post-SCID Treatment [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: From HCT to Month 6, Year 2, Year 5 and Year 8 Post-HCT]
• Time to Resolution of Infections Diagnosed Prior to HCT [Срок оценки: Through study completion, up to 8 years post-HCT]
• Incidence of New Infections Post-HCT [Срок оценки: 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 [Срок оценки: Baseline (Pre-HCT) to Year 1, Year 2, Year 5 and Year 8 Post-HCT]
• Longitudinal Analysis: Growth Percentile in Body Height [Срок оценки: Baseline (Pre-HCT), Year 1, Year 2, Year 5 and Year 8 Post-HCT]
• Longitudinal Analysis: Growth Percentile in Body Weight [Срок оценки: Baseline (Pre-HCT), Year 1, Year 2, Year 5 and Year 8 Post-HCT]
• Incidence of Acute Graft Versus Host Disease (GVHD) Post-HCT [Срок оценки: From HCT to Day 100 and Month 6 post-HCT]
• Incidence of Chronic Graft Versus Host Disease (GVHD) Post-HCT [Срок оценки: 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 [Срок оценки: 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) [Срок оценки: Baseline (Pre-SCID Treatment-HCT, ERT or GT),Year 1, Year 2, Year 4, Year 5 and Year 8 Post-SCID Treatment]

Критерии участия

Критерии включения

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.

Критерии исключения

-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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

США · 39 центров

• University of Alabama at Birmingham — Birmingham
• Phoenix Children's Hospital — Phoenix
• Children's Hospital Los Angeles — Los Angeles
• University of California, Los Angeles — Los Angeles
• Lucile Salter Packard Children's Hospital at Stanford — Palo Alto
• University of California San Francisco Children's Hospital — San Francisco
• Children's Hospital Denver — Denver
• Alfred I. duPont Hospital for Children/Nemours — Wilmington
• … и ещё 31 центр

Канада · 5 центров

• Alberta Children's Hospital — Calgary
• British Columbia Children's Hospital — Vancouver
• Cancer Care Manitoba — Winnipeg
• The Hospital for Sick Children — Toronto
• CHU Sainte-Justine — Montreal

Публикации

• Griffith LM, Cowan MJ, Kohn DB, Notarangelo LD, Puck JM, Schultz KR, Buckley RH, Eapen M, Kamani NR, O'Reilly RJ, Parkman R, Roifman CM, Sullivan KE, Filipovich AH, Fleisher TA, Shearer WT. Allogeneic hematopoietic cell transplantation for primary immune deficiency diseases: current status and critical needs. J Allergy Clin Immunol. 2008 Dec;122(6):1087-96. doi: 10.1016/j.jaci.2008.09.045. Epub 20 PMID 18992926
• Dvorak CC, Cowan MJ, Logan BR, Notarangelo LD, Griffith LM, Puck JM, Kohn DB, Shearer WT, O'Reilly RJ, Fleisher TA, Pai SY, Hanson IC, Pulsipher MA, Fuleihan R, Filipovich A, Goldman F, Kapoor N, Small T, Smith A, Chan KW, Cuvelier G, Heimall J, Knutsen A, Loechelt B, Moore T, Buckley RH. The natural history of children with severe combined immunodeficiency: baseline features of the first fifty pa PMID 23818196
• Shearer WT, Dunn E, Notarangelo LD, Dvorak CC, Puck JM, Logan BR, Griffith LM, Kohn DB, O'Reilly RJ, Fleisher TA, Pai SY, Martinez CA, Buckley RH, Cowan MJ. Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience. J Allergy Clin Immunol. 2014 Apr;133(4):1092-8. doi: 10.1016/j PMID 24290292
• Haddad E, Allakhverdi Z, Griffith LM, Cowan MJ, Notarangelo LD. Survey on retransplantation criteria for patients with severe combined immunodeficiency. J Allergy Clin Immunol. 2014 Feb;133(2):597-9. doi: 10.1016/j.jaci.2013.10.022. Epub 2013 Dec 10. No abstract available. PMID 24331379
• Griffith LM, Cowan MJ, Notarangelo LD, Kohn DB, Puck JM, Pai SY, Ballard B, Bauer SC, Bleesing JJ, Boyle M, Brower A, Buckley RH, van der Burg M, Burroughs LM, Candotti F, Cant AJ, Chatila T, Cunningham-Rundles C, Dinauer MC, Dvorak CC, Filipovich AH, Fleisher TA, Bobby Gaspar H, Gungor T, Haddad E, Hovermale E, Huang F, Hurley A, Hurley M, Iyengar S, Kang EM, Logan BR, Long-Boyle JR, Malech HL, M PMID 24139498
• Griffith LM, Cowan MJ, Notarangelo LD, Kohn DB, Puck JM, Shearer WT, Burroughs LM, Torgerson TR, Decaluwe H, Haddad E; workshop participants. Primary Immune Deficiency Treatment Consortium (PIDTC) update. J Allergy Clin Immunol. 2016 Aug;138(2):375-85. doi: 10.1016/j.jaci.2016.01.051. Epub 2016 Apr 22. PMID 27262745
• Pai SY, Logan BR, Griffith LM, Buckley RH, Parrott RE, Dvorak CC, Kapoor N, Hanson IC, Filipovich AH, Jyonouchi S, Sullivan KE, Small TN, Burroughs L, Skoda-Smith S, Haight AE, Grizzle A, Pulsipher MA, Chan KW, Fuleihan RL, Haddad E, Loechelt B, Aquino VM, Gillio A, Davis J, Knutsen A, Smith AR, Moore TB, Schroeder ML, Goldman FD, Connelly JA, Porteus MH, Xiang Q, Shearer WT, Fleisher TA, Kohn DB, PMID 25075835
• Griffith LM, Cowan MJ, Notarangelo LD, Puck JM, Buckley RH, Candotti F, Conley ME, Fleisher TA, Gaspar HB, Kohn DB, Ochs HD, O'Reilly RJ, Rizzo JD, Roifman CM, Small TN, Shearer WT; Workshop Participants. Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management. J Allergy Clin Immunol. 2009 Dec;124(6):1152-60.e12. doi: 10.1016/j.jaci.2009.10.022. PMID 20004776

Идентификаторы

NCT: NCT01186913 · DAIT RDCRN PIDTC-6901

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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