Patients Treated for Chronic Granulomatous Disease (CGD) Since 1995

NCT ID: NCT02082353

Last Updated: 2021-09-02

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 1480 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2014-06-30
• Study Completion Date: 2021-11-30

Brief Summary

Chronic granulomatous disease (CGD) is an inherited immune system abnormality in which bone marrow transplantation (BMT) 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 participants with CGD after a transplant and if possible, compare these results to participants who do not undergo a transplant.

Detailed Description

Chronic granulomatous disease (CGD) is an immune deficiency where the neutrophils (a type of white blood cell that kills bacteria and fungi) do no work properly. Some individuals with CGD have neutrophils that do not work at all, whereas others have neutrophils that work partially, but not normally. In the past (over 20 years ago), most individuals with CGD were managed with antibiotics and antifungal medications alone. As the science of blood and marrow transplant (BMT) improved, some with CGD started to receive a BMT. It remained controversial whether individuals with CGD should receive a BMT or medical management alone (antibiotics, antifungals, and other treatments that do not include BMT).

The aim of this natural history study is to better define the role of BMT compared to medical management of CGD. Specifically, what are the outcomes of BMT versus medical management alone, why do some individuals with CGD benefit from BMT, and what are the long-term outcomes of both approaches. Researchers are interested in how individuals with CGD who have no neutrophil function may differ from those with some neutrophil function, how the types of infections and inflammatory complications of CGD impact on survival and how BMT may improve these complications. There are also questions as to how the types of bacteria (called the microbiome) found in the gastrointestinal tract (colon, large intestine) of individuals with CGD influences certain inflammatory complications (such as colitis), and how BMT changes the microbiome in individuals with CGD. All of this will help doctors in the future to better treat patients with CGD.

This study includes a retrospective (looking back into the past), cross-sectional (one time collection of information and/or research testing) and a prospective (looking from today and into the future) component. These are known as longitudinal studies (e.g., looking at information of participants over time).

Persons with CGD who were born 1988 to the present day are eligible, regardless of whether they received a BMT (as long as the BMT was after 1995) or medical therapy only. Individuals who are newly diagnosed with CGD can also be enrolled and followed longitudinally (over time), to determine their outcome from the choice of therapy that is made. An important component of this study is the 'cross sectional' study, where participants with more than 3 years of follow-up after transplant or diagnosis are asked to provide additional research blood work, and information is gathered regarding long-term transplant outcomes such as infections, graft-versus-host disease, autoimmune diseases, and quality of life. In addition, the participants will be asked to provide stool samples to allow investigators to look at how certain bacteria found in the gut (called the microbiome) affect complications of CGD, such as gastrointestinal disease. This will allow primary immune deficiency investigators/doctors to better understand the outcomes of different therapeutic approaches and to best design new treatments and clinical trials in the future for children with CGD.

Conditions

Granulomatous Disease, Chronic

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: OTHER

Study Groups

Retrospective CGD Cohort

Longitudinal analysis

No interventions assigned to this group

Prospective CGD Cohort

Longitudinal analysis

No interventions assigned to this group

HCT CGD Cohort

Cross-sectional analysis

No interventions assigned to this group

Conventional Non-Transplant CGD Cohort

Longitudinal analysis

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• 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).

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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 stimulation index (SI) 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 classified 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 CGD 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.

Exclusion Criteria

• Presence of other primary immunodeficiency syndromes that do not meet the clinical and laboratory criteria for CGD.
• Rac2 Deficiency
• Myeloperoxidase 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).

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Rare Diseases Clinical Research Network

NETWORK

Sponsor Role: collaborator

Primary Immune Deficiency Treatment Consortium (PIDTC)

OTHER

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jennifer M. Puck, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Donald B. Kohn, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, Los Angeles

Locations

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

UCLA

Los Angeles, California, United States

Lucile Salter Packard Children's Hospital at Stanford

Palo Alto, California, United States

University of California (UCSF) Benioff Children's Hospital

San Francisco, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Alfred I. duPont Hospital for Children/Nemours

Wilmington, Delaware, United States

Children's National Medical Center, Washington DC

Washington D.C., District of Columbia, United States

Johns Hopkins All Children's Hospital - St. Petersburg, FL

St. Petersburg, Florida, United States

Children's Healthcare of Atlanta, Emory University

Atlanta, Georgia, United States

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

Children's Hospital of New Orleans at LSUHSC

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 Hospital/ St. Louis University

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

Rainbow Babies/ University Hospitals Case Medical Center

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 at Dallas

Dallas, Texas, United States

Texas Children's Hospital, Baylor College of Medicine

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

Children's Hospital of Wisconsin-Milwaukee

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 St. Justine

Montreal, Quebec, Canada

Countries

United States; Canada

References

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Reference Type: RESULT

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Reference Type: RESULT

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Reference Type: RESULT

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Reference Type: RESULT

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Reference Type: DERIVED

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Related Links

https://www.niaid.nih.gov

National Institute of Allergy and Infectious Diseases (NIAID)

https://www.rarediseasesnetwork.org/spotlight/v9i1/PIDTC

Primary Immune Deficiency Treatment Consortium (PIDTC)

https://www.rarediseasesnetwork.org/research-groups

Rare Diseases Clinical Research Network

Other Identifiers

U54AI082973

Identifier Type: NIH

Identifier Source: secondary_id

View Link

DAIT RDCRN PIDTC-6903

Identifier Type: -

Identifier Source: org_study_id