Patients Treated for SCID (1968-Present)

ADA-SCID Clinical Trial

Official title:

A Retrospective and Cross-Sectional Analysis of Patients Treated for SCID Since January 1,1968 (RDCRN PIDTC-6902)

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT01346150
• Other study ID #: DAIT RDCRN PIDTC-6902
• Status: Enrolling by invitation
• Start date: May 15, 2011
• Est. completion date: August 2023

Study information

• Verified date: November 2020
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Individuals with a past diagnosis of severe combined immune deficiency (including many cases of "leaky SCID", Omenn syndrome, and reticular dysgenesis) who have undergone blood and marrow transplant, gene therapy, or enzyme replacement in the past may be eligible for this study. The purpose of study is to look backwards at what has already been done in the. Over 800 patients with SCID are expected to be enrolled, making this one of the largest studies ever to describe outcomes for patients with SCID treated at many different hospitals around North America.

Description:

One of the most important components of this study is the "cross sectional" aspect. Patients who have received their treatments (BMT, gene therapy, enzyme replacement) many years ago are asked to come back to the hospital where they were treated. During this visit, additional research bloodwork is drawn, and information is gathered regarding long-term transplant outcomes such as infections, graft-versus-host disease, autoimmune diseases, and quality of life. This will allow PIDTC researchers to better understand long-term outcomes from procedures that occurred many years ago (sometimes over 30 years ago). This will help researchers to best design new treatments and clinical trials in the future for children with SCID.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 1007
• Est. completion date: August 2023
• Est. primary completion date: August 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

Strata A, B, and C (Part 1 - Retrospective Study)-

• Individuals with Severe Combined Immune Deficiency (SCID) diagnosis who:

--were treated at a location participating in this consortium from 1968 until present, and

--are not enrolled in RDCRN PIDTC-6901 (ClinicalTrials.gov ID: NCT01186913).

• Subjects who received HCT/GT/ERT prior to the present date are eligible for the retrospective study. The enrollment criteria for subjects who died prior to definitive therapy are the same as for Strata A, B and C.

Stratum A, Typical SCID:

• Individuals who meet the following inclusion criteria and who received HCT are eligible for enrollment into Stratum A 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 cells of maternal origin present.

• If maternal cells are present but the patient does not meet criteria for very low T cell function as defined, the assigned reviewers for the potential subject, and if necessary, the full PID-SCID RP will review the laboratory report to determine if criteria of maternal engraftment are met for Protocol 6902.

• Laboratory report of testing for maternal engraftment is required, for evaluation by the PID-SCID RP.

Stratum B, Leaky SCID, Omenn Syndrome, Reticular Dysgenesis:

Individuals who meet the following criteria are eligible for enrollment into Stratum B of the study:

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 < 50% of lower limit of normal T cell function as measured by response to CD3/CD28 antibody, b) Absent or < 30% lower limit of normal proliferative responses to candida and tetanus toxoid antigens postvaccination or exposure,

• AND at least one of the following (a through e):

1. Reduced number of CD3 T cells,

2. > 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 < 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 at least one hypomorphic mutation in an autosomal SCID-causing gene.

d) Low 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,

• AND does not have known selective loss of lymphocytes, Ataxia- Telangiectasia, or congenital heart defect associated with lymphopenia, unless a SCID genotype is also present.

Omenn Syndrome (OS):

• Generalized skin rash,

• Maternal engraftment tested for and not detected,

• Absent or low (up to 30% of normal) T cell proliferation to antigens to which the patient has been exposed.

• If the proliferation to antigen was not performed, but at least 4 of the following 10 supportive criteria, at least one of which must be among those marked with an asterisk (*) are present, the patient is eligible: hepatomegaly; splenomegaly; lymphadenopathy; elevated IgE; elevated absolute eosinophil count; *oligoclonal T cells measured by CDR3 length or flow cytometry >80% of CD4+ T cells are CD45RO+ ;*proliferation to PHA is reduced <50% of lower limit of normal or SI <30; *proliferative response in mixed leukocyte reaction is reduced to increment cpm < 20% or SI <20; hypomorphic mutation to SCID causing gene; low TRECs and/or percentage of CD 4+/ RA+/CD31+; or CD4+/RA+/CD62L+ cells below the lower limit of normal.

Reticular Dysgenesis (RD):

• Absence or very low number of T cells (CD3 T cells <300/microliter),

• No or very low (<10% of lower limit of normal) T cell function (as measured by response to phytohemagglutinin (PHA),

• Severe congenital neutropenia (absolute neutrophil count <200/microliter),

• AND at least one of the following:

• Sensorineural deafness and/or absence of granulopoiesis at bone marrow examination and/or a deleterious AK2 mutation,

• absence of granulopoiesis on bone marrow examination; a pathogenic mutation in the adenylate kinase 2 (AK2) gene identified.

Stratum C, SCID with Non-HCT Treatments:

-Individuals who meet the following criteria and were treated with PEG-ADA or gene therapy with autologous modified cells are eligible for enrollment into Stratum C (SCID with non-HCT treatments) of the study-

• Any SCID patient previously treated with a thymus transplant (includes intention to treat with HCT, as well as PEG-ADA ERT or gene therapy).

Strata A, B, and C (Part 2 - Cross-Sectional Study):

Patient inclusion criteria for the cross sectional study: Eligibility for Strata A, B and C are the same as for the retrospective study except that all the patients in the cross-sectional study are currently surviving and are at least 2 years post the most recent class of therapy.

Exclusion Criteria:

Parts 1 and 2 - Retrospective and Cross-Sectional Studies -

• Lack of appropriate testing to rule out HIV infection after 1997 (p24 antigen or more sensitive) or other cause of secondary immunodeficiency,

• Presence of DiGeorge syndrome,

• Most patients with other PIDs such as nucleoside phosphorylase deficiency, ZAP70 deficiency, CD40 ligand deficiency, NEMO deficiency, XLP, cartilage hair hypoplasia or ataxia telangiectasia will not meet the inclusion criteria for Stratum A, B, or C above; however, a patient with one of the above may meet the inclusion criteria for Stratum B and if so will be included-

• MHC Class I and MHC Class II antigen deficiency are excluded,

• Metabolic conditions that imitate SCID or related disorders such as folate transporter deficiency, severe zinc deficiency, transcobalamin deficiency.

Related Conditions & MeSH terms

• ADA-SCID
• Leaky SCID
• Omenn Syndrome
• Reticular Dysgenesis
• SCID
• Severe Combined Immunodeficiency
• XSCID

Locations

Country	Name	City	State
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	CHU St. Justine	Montréal	Quebec
Canada	The Hospital for Sick Children (SickKids)	Toronto	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
Canada	Cancer Care Manitoba	Winnipeg	Manitoba
United States	University of Michigan Health System	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta/Emory University School of Medicine	Atlanta	Georgia
United States	NIH Clinical Center Genetic Immunotherapy Section	Bethesda	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Children's Hospital Boston	Boston	Massachusetts
United States	Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	University of Texas Southwestern Medical Center Dallas	Dallas	Texas
United States	Children's Hospital Denver:Center for Cancer and Blood Disorders	Denver	Colorado
United States	Duke University Medical Center: Department of Pediatrics, Division of Allergy/Immunology	Durham	North Carolina
United States	Hackensack University Medical Center: Department of Pediatrics	Hackensack	New Jersey
United States	Texas Children's Hospital	Houston	Texas
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Mattel Children's Hospital UCLA: Division of Pediatric Hematology/Oncology	Los Angeles	California
United States	University of Wisconsin/ American Family Children's Hospital	Madison	Wisconsin
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota Medical Center	Minneapolis	Minnesota
United States	Children's Hospital/Louisiana State University Health Sciences Center	New Orleans	Louisiana
United States	Memorial Sloan-Kettering Cancer Center: Department of Pediatrics	New York	New York
United States	Lucile Salter Packard Children's Hospital at Stanford	Palo Alto	California
United States	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Oregon Health & Science University: Pediatric Hematology/Oncology	Portland	Oregon
United States	SSM Cardinal Glennon Children's Medical Center	Saint Louis	Missouri
United States	Washington University St Louis Children's Hospital	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Medical Center/University of Utah	Salt Lake City	Utah
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	University of California San Francisco Children's Hospital	San Francisco	California
United States	Fred Hutchinson Cancer Research Center: Clinical Research Division and Pediatric Stem Cell Transplantation Center	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	National Center for Advancing Translational Science (NCATS), Primary Immune Deficiency Treatment Consortium (PIDTC)

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (12)

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 — View Citation

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, Ca — View Citation

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. — View Citation

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, Fle — View Citation

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. do — View Citation

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 defi — View Citation

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. — View Citation

Haddad E, Logan BR, Griffith LM, Buckley RH, Parrott RE, Prockop SE, Small TN, Chaisson J, Dvorak CC, Murnane M, Kapoor N, Abdel-Azim H, Hanson IC, Martinez C, Bleesing JJH, Chandra S, Smith AR, Cavanaugh ME, Jyonouchi S, Sullivan KE, Burroughs L, Skoda-S — View Citation

Kohn DB, Hershfield MS, Puck JM, Aiuti A, Blincoe A, Gaspar HB, Notarangelo LD, Grunebaum E. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. J Allergy Clin Immunol. 2019 Mar;143(3):852-8 — View Citation

Miggelbrink AM, Logan BR, Buckley RH, Parrott RE, Dvorak CC, Kapoor N, Abdel-Azim H, Prockop SE, Shyr D, Decaluwe H, Hanson IC, Gillio A, Dávila Saldaña BJ, Eibel H, Hopkins G, Walter JE, Whangbo JS, Kohn DB, Puck JM, Cowan MJ, Griffith LM, Haddad E, O'Re — View Citation

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 — View Citation

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, — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Retrospective Study - Part 1	Overall survival	1, 5, 10, 20, >20 years
Primary	Cross-Sectional Study - Part 2	Full immune reconstitution	2 to > 20 years
Secondary	Retrospective Study Part 1	Immune reconstitution and clinical outcomes	1 year to > 20 years
Secondary	Retrospective Study - Part 1	Engraftment	3 months to >20 years
Secondary	Cross-Sectional Study - Part 2	Current state of lineage-specific chimerism	2 to >20 years
Secondary	Cross-Sectional Study - Part 2	Current status of health	2 to >20 years

External Links

•   Division of Allergy, Immunology, and Transplantation (DAIT)
•   National Center for Advancing Translational Sciences (NCATS)
•   National Institute of Allergy and Infectious Diseases (NIAID)
•   Primary Immune Deficiency Treatment Consortium (PIDTC)