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Patients Treated for SCID (1968-Present)

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ClinicalTrials.gov Identifier: NCT01346150
Recruitment Status : Recruiting
First Posted : May 2, 2011
Last Update Posted : November 9, 2017
Sponsor:
Collaborators:
Rare Diseases Clinical Research Network
Primary Immune Deficiency Treatment Consortium
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Study Description
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Brief Summary:
People with Primary Immune Deficiency (PID) may develop severe, life-threatening infections as a result of inherited defects in the genes that normally instruct blood-forming cells to develop and to fight infections. PID diseases include Severe Combined Immune Deficiency (SCID), leaky SCID, Omenn syndrome (OS), and Reticular Dysgenesis (RD). PIDs may be treated by transplantation of bone marrow stem cells from a healthy person or, in some cases, by enzyme replacement or by gene therapy. Patients with SCID were among the first to receive bone marrow stem cell (also called hematopoietic cells) transplantation (HCT) more than 40 years ago, and HCT is the standard treatment today for this group of diseases. Since PID diseases are rare, there are not enough patients at any single center to determine the full range of causes, natural history, or best methods of treatment. For this research study many PID centers across North America have organized into the Primary Immune Deficiency Treatment Consortium (PIDTC) to pool their experience and study PIDs together. Researchers will collect information on your general health, psychological and developmental health, and the current status of your immune system to help better define future approaches to PID treatments.

Condition or disease
SCID ADA-SCID XSCID Leaky SCID Omenn Syndrome Reticular Dysgenesis

Study Design
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Study Type : Observational
Estimated Enrollment : 1146 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: A Retrospective and Cross-Sectional Analysis of Patients Treated for SCID Since January 1,1968 (RDCRN PIDTC-6902)
Study Start Date : May 2011
Estimated Primary Completion Date : August 2019
Estimated Study Completion Date : August 2019

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort
Stratum A
SCID, ADA-SCID, and XSCID who received a transplant
Stratum B
Leaky SCID, Omenn Syndrome, and Reticular Dysgenesis who received a transplant
Stratum C
SCID who received PEG ADA or gene therapy


Outcome Measures
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Primary Outcome Measures :
  1. Retrospective Study - Part 1 [ Time Frame: 1, 5, 10, 20, >20 years ]
    Overall survival

  2. Cross-Sectional Study - Part 2 [ Time Frame: 2 to > 20 years ]
    Full immune reconstitution


Secondary Outcome Measures :
  1. Retrospective Study Part 1 [ Time Frame: 1 year to > 20 years ]
    Immune reconstitution and clinical outcomes

  2. Retrospective Study - Part 1 [ Time Frame: 3 months to >20 years ]
    Engraftment

  3. Cross-Sectional Study - Part 2 [ Time Frame: 2 to >20 years ]
    Current state of lineage-specific chimerism

  4. Cross-Sectional Study - Part 2 [ Time Frame: 2 to >20 years ]
    Current status of health


Biospecimen Retention:   Samples With DNA
Biospecimens may include blood, other tissues (e.g., buccal swab or brushing), and/or bone marrow.

Eligibility Criteria
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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Individuals with diagnosis of SCID or SCID variants treated at Participating Consortium Centers from 1968-Present
Criteria

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 (Classic 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 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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01346150


  Show 36 Study Locations
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Rare Diseases Clinical Research Network
Primary Immune Deficiency Treatment Consortium
Investigators
Principal Investigator: Morton J Cowan, MD UCSF Children's Hospital
Principal Investigator: Elie Haddad, MD St. Justine's Hospital
More Information
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Additional Information:
The National Institute of Allergy and Infectious Diseases (NIAID)  This link exits the ClinicalTrials.gov site
The Rare Diseases Clinical Research Network (RDCRN)  This link exits the ClinicalTrials.gov site
Primary Immune Deficiency Treatment Consortium (PIDTC)  This link exits the ClinicalTrials.gov site

Publications of Results:

Other Publications:

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01346150     History of Changes
Other Study ID Numbers: DAIT RDCRN PIDTC-6902
First Posted: May 2, 2011    Key Record Dates
Last Update Posted: November 9, 2017
Last Verified: November 2017

Additional relevant MeSH terms:
Severe Combined Immunodeficiency
Infant, Newborn, Diseases
DNA Repair-Deficiency Disorders
 Metabolic Diseases
Immunologic Deficiency Syndromes
Immune System Diseases