Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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ENROLLING_BY_INVITATION
690 participants
OBSERVATIONAL
2010-09-02
2028-09-30
Brief Summary
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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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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.
Conditions
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Keywords
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Study Design
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COHORT
PROSPECTIVE
Study Groups
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Stratum A: Typical SCID +HCT
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.
No interventions assigned to this group
Stratum B: Atypical SCID +HCT
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.
No interventions assigned to this group
Stratum C:SCID +Non-HCT
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)
No interventions assigned to this group
Eligibility Criteria
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Inclusion Criteria
* 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
* 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.
ALL
No
Sponsors
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Primary Immune Deficiency Treatment Consortium (PIDTC)
OTHER
Office of Rare Diseases (ORD)
NIH
National Center for Advancing Translational Sciences (NCATS)
NIH
National Institute of Allergy and Infectious Diseases (NIAID)
NIH
Responsible Party
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Principal Investigators
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Christopher C. Dvorak, MD
Role: PRINCIPAL_INVESTIGATOR
UCSF Children's Hospital
Morton J. Cowan, MD
Role: PRINCIPAL_INVESTIGATOR
UCSF Children's Hospital
Locations
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University of Alabama at Birmingham
Birmingham, Alabama, United States
Phoenix Children's Hospital
Phoenix, Arizona, United States
Children's Hospital Los Angeles
Los Angeles, California, United States
University of California, Los Angeles
Los Angeles, California, United States
Lucile Salter Packard Children's Hospital at Stanford
Palo Alto, California, United States
University of California San Francisco Children's Hospital
San Francisco, California, United States
Children's Hospital Denver
Denver, Colorado, United States
Alfred I. duPont Hospital for Children/Nemours
Wilmington, Delaware, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
Johns Hopkins All Children's Hospital
St. Petersburg, Florida, United States
Children's Healthcare of Atlanta/Emory University School of Medicine
Atlanta, Georgia, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, United States
Children's Hospital/Louisiana State University Health Sciences Center
New Orleans, Louisiana, United States
NIH Clinical Center Genetic Immunotherapy Section
Bethesda, Maryland, United States
Children's Hospital Boston
Boston, Massachusetts, United States
University of Michigan Health System
Ann Arbor, Michigan, United States
University of Minnesota Medical Center
Minneapolis, Minnesota, United States
Mayo Clinic Hospital
Rochester, Minnesota, United States
Cardinal Glennon Children's Medical Center
St Louis, Missouri, United States
Washington University St Louis Children's Hospital
St Louis, Missouri, United States
Hackensack University Medical Center
Hackensack, New Jersey, United States
Memorial Sloan-Kettering Cancer Center
New York, New York, United States
University of Rochester Medical Center/ Golisano Children's Hospital
Rochester, New York, United States
New York Medical College, Maria Fareri Children's Hospital
Valhalla, New York, United States
Duke University
Durham, North Carolina, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
University Hospitals-Rainbow Babies and Children's Hospital
Cleveland, Ohio, United States
Nationwide Children's Hospital
Columbus, Ohio, United States
Oregon Health and Science University
Portland, Oregon, United States
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States
St. Jude Children's Research Hospital
Memphis, Tennessee, United States
University of Texas Southwestern Medical Center/Children's of Dallas
Dallas, Texas, United States
Texas Children's Hospital
Houston, Texas, United States
Methodist Children's Hospital of South Texas/Texas Transplant Institute
San Antonio, Texas, United States
Primary Children's Medical Center/University of Utah
Salt Lake City, Utah, United States
Seattle Children's Research Institute
Seattle, Washington, United States
University of Wisconsin/ American Family Children's Hospital
Madison, Wisconsin, United States
Medical College of Wisconsin
Milwaukee, Wisconsin, United States
Alberta Children's Hospital
Calgary, Alberta, Canada
British Columbia Children's Hospital
Vancouver, British Columbia, Canada
Cancer Care Manitoba
Winnipeg, Manitoba, Canada
The Hospital for Sick Children
Toronto, Ontario, Canada
CHU Sainte-Justine
Montreal, Quebec, Canada
Countries
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References
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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 2008 Nov 6.
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 patients of the primary immune deficiency treatment consortium prospective study 6901. J Clin Immunol. 2013 Oct;33(7):1156-64. doi: 10.1007/s10875-013-9917-y. Epub 2013 Jul 2.
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.jaci.2013.09.044. Epub 2013 Nov 28.
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.
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, McGhee SA, Modell F, Modell V, Ochs HD, O'Reilly RJ, Parkman R, Rawlings DJ, Routes JM, Shearer WT, Small TN, Smith H, Sullivan KE, Szabolcs P, Thrasher A, Torgerson TR, Veys P, Weinberg K, Zuniga-Pflucker JC; workshop participants. Primary Immune Deficiency Treatment Consortium (PIDTC) report. J Allergy Clin Immunol. 2014 Feb;133(2):335-47. doi: 10.1016/j.jaci.2013.07.052. Epub 2013 Oct 15.
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.
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, Puck JM, Notarangelo LD, Cowan MJ, O'Reilly RJ. Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med. 2014 Jul 31;371(5):434-46. doi: 10.1056/NEJMoa1401177.
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.
Dvorak CC, Haddad E, Buckley RH, Cowan MJ, Logan B, Griffith LM, Kohn DB, Pai SY, Notarangelo L, Shearer W, Prockop S, Kapoor N, Heimall J, Chaudhury S, Shyr D, Chandra S, Cuvelier G, Moore T, Shenoy S, Goldman F, Smith AR, Sunkersett G, Vander Lugt M, Caywood E, Quigg T, Torgerson T, Chandrakasan S, Craddock J, Davila Saldana BJ, Gillio A, Shereck E, Aquino V, DeSantes K, Knutsen A, Thakar M, Yu L, Puck JM. The genetic landscape of severe combined immunodeficiency in the United States and Canada in the current era (2010-2018). J Allergy Clin Immunol. 2019 Jan;143(1):405-407. doi: 10.1016/j.jaci.2018.08.027. Epub 2018 Sep 5.
Cuvelier GDE, Logan BR, Prockop SE, Buckley RH, Kuo CY, Griffith LM, Liu X, Yip A, Hershfield MS, Ayoub PG, Moore TB, Dorsey MJ, O'Reilly RJ, Kapoor N, Pai SY, Kapadia M, Ebens CL, Forbes Satter LR, Burroughs LM, Petrovic A, Chellapandian D, Heimall J, Shyr DC, Rayes A, Bednarski JJ, Chandra S, Chandrakasan S, Gillio AP, Madden L, Quigg TC, Caywood EH, Davila Saldana BJ, DeSantes K, Eissa H, Goldman FD, Rozmus J, Shah AJ, Vander Lugt MT, Thakar MS, Parrott RE, Martinez C, Leiding JW, Torgerson TR, Pulsipher MA, Notarangelo LD, Cowan MJ, Dvorak CC, Haddad E, Puck JM, Kohn DB. Outcomes following treatment for ADA-deficient severe combined immunodeficiency: a report from the PIDTC. Blood. 2022 Aug 18;140(7):685-705. doi: 10.1182/blood.2022016196.
Dorsey MJ, Wright NAM, Chaimowitz NS, Davila Saldana BJ, Miller H, Keller MD, Thakar MS, Shah AJ, Abu-Arja R, Andolina J, Aquino V, Barnum JL, Bednarski JJ, Bhatia M, Bonilla FA, Butte MJ, Bunin NJ, Chandra S, Chaudhury S, Chen K, Chong H, Cuvelier GDE, Dalal J, DeFelice ML, DeSantes KB, Forbes LR, Gillio A, Goldman F, Joshi AY, Kapoor N, Knutsen AP, Kobrynski L, Lieberman JA, Leiding JW, Oshrine B, Patel KP, Prockop S, Quigg TC, Quinones R, Schultz KR, Seroogy C, Shyr D, Siegel S, Smith AR, Torgerson TR, Vander Lugt MT, Yu LC, Cowan MJ, Buckley RH, Dvorak CC, Griffith LM, Haddad E, Kohn DB, Logan B, Notarangelo LD, Pai SY, Puck J, Pulsipher MA, Heimall J. Infections in Infants with SCID: Isolation, Infection Screening, and Prophylaxis in PIDTC Centers. J Clin Immunol. 2021 Jan;41(1):38-50. doi: 10.1007/s10875-020-00865-9. Epub 2020 Oct 2.
Heimall J, Logan BR, Cowan MJ, Notarangelo LD, Griffith LM, Puck JM, Kohn DB, Pulsipher MA, Parikh S, Martinez C, Kapoor N, O'Reilly R, Boyer M, Pai SY, Goldman F, Burroughs L, Chandra S, Kletzel M, Thakar M, Connelly J, Cuvelier G, Davila Saldana BJ, Shereck E, Knutsen A, Sullivan KE, DeSantes K, Gillio A, Haddad E, Petrovic A, Quigg T, Smith AR, Stenger E, Yin Z, Shearer WT, Fleisher T, Buckley RH, Dvorak CC. Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study. Blood. 2017 Dec 21;130(25):2718-2727. doi: 10.1182/blood-2017-05-781849. Epub 2017 Oct 11.
Related Links
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Primary Immune Deficiency Treatment Consortium (PIDTC) featured highlights
Division of Allergy, Immunology, and Transplantation (DAIT)
National Institute of Allergy and Infectious Diseases (NIAID)
Rare Diseases Clinical Research Network (RDCRN)
National Center for Advancing Translational Science (NCATS)
Other Identifiers
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DAIT RDCRN PIDTC-6901
Identifier Type: -
Identifier Source: org_study_id
NCT02108067
Identifier Type: -
Identifier Source: nct_alias