Patients Treated for Chronic Granulomatous Disease (CGD) Since 1995

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Collaborators:
Primary Immune Deficiency Treatment Consortium (PIDTC)
Rare Diseases Clinical Research Network (RDCRN)
Pediatric Blood and Marrow Transplant Consortium (PBMTC)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT02082353
First received: March 6, 2014
Last updated: June 27, 2014
Last verified: June 2014
  Purpose

Chronic granulomatous disease (CGD) is an inherited immune system abnormality in which bone marrow transplantation has been shown to be curative. However the risks of transplantation are high and not all patients with CGD may need to undergo this high risk procedure. This study will determine the long term medical condition and daily functioning of patients with CGD after a transplant and if possible, compare these results to patients who do not undergo a transplant.

This multi-center study combines a longitudinal and cross-sectional evaluation (both retro and prospectively) of subjects with confirmed CGD who have already received hematopoietic cell transplant (HCT) since 1995 or who will receive HCT during the study period. This study will investigate which subjects benefit most from HCT, and the overall outcomes in CGD patients with and without transplant. The study aims to identify variables contributing to best outcomes of HCT in subjects with CGD.


Condition
Granulomatous Disease, Chronic

Study Type: Observational
Study Design: Observational Model: Case Control
Official Title: Analysis of Patients Treated for Chronic Granulomatous Disease Since January 1, 1995

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Death [ Time Frame: HCT to date of death, up to an expected average of 3 years ] [ Designated as safety issue: Yes ]
    The event analyzed is death from any cause. The time from HCT to death or last follow up will be analyzed. Cause of death will also be collected. Surviving patients will be censored at the time of last observation.


Secondary Outcome Measures:
  • Engraftment [ Time Frame: an expected average of 3 years ] [ Designated as safety issue: No ]
    Engraftment will be measures in whole blood using either fluorescent in situ hybridization (FISH) for sex chromosomes or short tandem repeat PCR (STRs) in whole blood.

  • Quality of Life Measures [ Time Frame: an expected average of 3 years ] [ Designated as safety issue: No ]

    Age appropriate testing will be performed at the cross-sectional visit in patients surviving at least two years posttransplant:

    • Peds QL Family Impact Module, Parent Report
    • Peds QL Infant Scales Module (ages 1-24 months), Parent Report
    • Peds QL Generic Core Scales for Toddlers (ages 2-4 yr), Parent Report
    • Peds QL Generic Core Scales (ages 5-25 yr), Child/Parent Reports
    • Peds QL Transplant Module
    • SF-36 (adult)
    • FACT BMT (adult)

  • Infections [ Time Frame: an expected average of 3 years ] [ Designated as safety issue: Yes ]
    CGD or transplant-related and transplant-related infection

  • Autoimmune or inflammatory complications [ Time Frame: an expected average of 3 years ] [ Designated as safety issue: Yes ]
    - For HCT subjects, inflammation (inflammatory complications) includes chronic GVHD


Biospecimen Retention:   Samples With DNA

Peripheral blood, skin swabs and/or stool samples


Estimated Enrollment: 1480
Study Start Date: June 2014
Estimated Study Completion Date: August 2019
Estimated Primary Completion Date: August 2019 (Final data collection date for primary outcome measure)
Groups/Cohorts
Longitudinal analysis: Retrospective CGD Cohort
Longitudinal analysis: Prospective CGD Cohort
Cross-sectional Analysis: HCT CGD Cohort
Longitudinal Analysis: Conventional Non-Transplant CGD Cohort

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Institutions participating in Rare Diseases Clinical Research Network (RDCRN)

Criteria

Inclusion Criteria:

  • Participant Inclusion Criteria (Part 1 - Longitudinal Analysis)

    • CGD Patients Undergoing Transplant 1995 to Present with Birth Year In or After 1988

      1. CGD Patients will be Defined by both Defective Neutrophil NADPH Oxidase Function and by Clinical History Consistent with CGD

        Patients must have BOTH of:

        A functional assay demonstrating abnormal NADPH oxidase function (see A below); AND Clinical history consistent with CGD (see B below).

        *************************************************************************

        Patients must have BOTH "A" and "B":

        A. Function: Assays of NADPH Oxidase Function

        I. Dihydrorhodamine (DHR) Assay:

        • Blood sample was obtained at a time when patient was clinically stable and not critically ill, with control samples performed simultaneously indicating a qualified assay; and
        • Assay unequivocally demonstrates CGD with an SI < 35 or equivalent. Assay report, including mean fluorescence intensity (MFI) from unstimulated and stimulated samples and gating strategy, must be de-identified and provided. OR

        II. Nitroblue Tetrazolium Oxidation Test (NBT):

        o Diagnostic of CGD (reported as reduced granulocyte oxidative response). Report must be de-identified and provided. AND

        B. Clinical History: One or More of the Following:

        • Severe and/or recurrent infection (liver, perirectal or lung abscess; pneumonia; adenitis; or osteomyelitis) due to, for example, Staphylococcus aureus, Burkholderia sp, Serratia marcescens, non-albicans Candida sp, Aspergillus sp or other mold; or Nocardia sp or other deep tissue infection characteristic of CGD
        • Sterile granulomatous disease in respiratory, gastrointestinal or urogenital tracts; or Crohn's disease-like colitis
        • A family history consistent with either X-linked or autosomal recessive CGD

        In cases where either functional assay (A) or history (B) is equivocal, one or more of the following may be used to confirm a diagnosis of CGD:

        C. Absent or significantly reduced in expression or abnormal size of any of the 5 phox components (gp91 phox, p47 phox, p22 phox, p67phox, and p40phox) of NADPH oxidase, by either:

        • Western blot
        • Northern blot OR D. Mutation in a gene encoding one of the 5 phox components (gp91 phox, p47 phox, p22 phox, p67 phox, and p40 phox) of NADPH oxidase that is predictive of a decreased or absent oxidative burst. (Nonsense, frameshift, or previously described missense mutation associated with CGD).

        Molecular Diagnosis is Desirable In addition, molecular diagnosis (gene sequencing and expression analysis) of CGD is desirable and should be performed when possible.

      2. Further Characterization of Oxidase Level, Longitudinal Study, Prospective Cohort Patients who are to undergo transplantation during the study period must be further characterized as oxidase-null or oxidase positive by level of oxidase production by either:

        • DHR assay stimulation Index: where SI ≤ 2.5 will be classified as oxidase-null CGD. Those with SI > 2.5 will be classified as oxidase positive CGD. A single validated test that is accepted by the PID-CGD Review Panel is adequate, but testing on two occasions for validation is desirable. OR
        • Ferricytochrome C reduction assay of granulocytes with O2 < 2.3 nmoles /106 cells/h classifed as oxidase-null CGD. A single validated test that is accepted by the PID-CGD Review Panel is adequate, but testing on two occasions for validation is desirable.

        OR

        o Genetic sequencing reporting a mutation that is unequivocally associated to absent oxidase production. (e.g. null mutations) will be classified as oxidase-null CGD (See discussion in Appendix I for how family history, genotype and CGD mutation information will be applied to assigning patients lacking any quantitative oxidase activity measurements to residual oxidase-null or residual oxidase-positive groups).

      3. Longitudinal Study, Retrospective Cohort Patients who have already been transplanted will be included regardless of whether further characterization by oxidase level (or genotype/mutation data) is possible or not.
    • Non-Transplanted CGD Patients with Birth Year In or After 1988 A non-transplant (conventional therapy) group of GGD subjects will be enrolled in the longitudinal study. The non-transplant subjects will be selected from the potentially eligible (retrospective) patient cohort with diagnosis of CGD treated with conventional non-transplant therapy. Participating sites will enter their entire retrospective cohort of CGD patients having birth year in or after 1988 into the registration cohort for this protocol. Baseline for both non-transplant subjects and HCT subjects for the purpose of comparing survival will be the year of birth. However, for non-transplant subjects, many of the detailed analyses such as infection and autoimmune complication rates will be assessed in the year preceding the date of last contact.
  • Participant Inclusion Criteria (Part 2 - Cross-Sectional Analysis) To participate in the Cross-Sectional Analysis, patients must have previously been enrolled into the Longitudinal Analysis of Protocol 6903. All transplanted subjects in the Cross-Sectional Analysis are surviving and shall have at least 3 years of follow-up post-transplant to be included. Non-transplanted CGD subjects will become eligible for consideration for the Cross-Sectional Analysis if they were eligible and enrolled in the retrospective cohort of the Longitudinal Analysis, and if/when they are > 3 years post-diagnosis of CGD. Provision of written informed consent will be required for inclusion in the Cross-Sectional Analysis.

Exclusion Criteria:

  • Participant Exclusion Criteria (Longitudinal and Cross- Sectional Analyses)

    • Presence of other primary immunodeficiency syndromes that do not meet the clinical and laboratory criteria for CGD.
    • Rac2 Deficiency
    • MPO Deficiency
    • Glutathione deficiency
    • Leukocyte adhesion deficiency syndrome
  • Non-transplant subjects:

    • The above exclusions pertain.
    • In addition, non-transplant subjects will be excluded if the only assessment of oxidase function available is the nitroblue tetrazolium (NBT) test (a non-quantitative test).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02082353

  Show 29 Study Locations
Sponsors and Collaborators
Primary Immune Deficiency Treatment Consortium (PIDTC)
Rare Diseases Clinical Research Network (RDCRN)
Pediatric Blood and Marrow Transplant Consortium (PBMTC)
Investigators
Principal Investigator: Elizabeth M. Kang, MD National Institute of Allergy and Infectious Diseases (NIAID)
Principal Investigator: Harry L Malech, MD National Institute of Allergy and Infectious Diseases (NIAID)
Principal Investigator: Luigi D Notarangelo, MD Children's Hospital Boston
  More Information

Additional Information:
No publications provided

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02082353     History of Changes
Other Study ID Numbers: DAIT RDCRN PIDTC-6903
Study First Received: March 6, 2014
Last Updated: June 27, 2014
Health Authority: United States: Federal Government
United States: Institutional Review Board

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Granulomatous Disease, Chronic
Hematopoietic Stem Cell Transplantation

Additional relevant MeSH terms:
Chronic Disease
Granuloma
Granulomatous Disease, Chronic
Disease Attributes
Pathologic Processes
Lymphoproliferative Disorders
Lymphatic Diseases
Phagocyte Bactericidal Dysfunction
Leukocyte Disorders
Hematologic Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Immunologic Deficiency Syndromes
Immune System Diseases

ClinicalTrials.gov processed this record on September 30, 2014