Patients Treated for Chronic Granulomatous Disease (CGD) Since 1995

Granulomatous Disease, Chronic Clinical Trial

Official title:

Analysis of Patients Treated for Chronic Granulomatous Disease Since January 1, 1995

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT02082353
• Other study ID #: DAIT RDCRN PIDTC-6903
• Secondary ID: U54AI082973
• Status: Enrolling by invitation
• Start date: June 2014
• Est. completion date: November 2021

Study information

• Verified date: September 2021
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 1480
• Est. completion date: November 2021
• Est. primary completion date: November 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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 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.

• 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

• 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).

Related Conditions & MeSH terms

• Chronic Disease
• Granuloma
• Granulomatous Disease, Chronic

Locations

Country	Name	City	State
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	CHU St. Justine	Montreal	Quebec
Canada	The Hospital for Sick Children	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	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
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	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
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	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas
United States	Duke University	Durham	North Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Texas Children's Hospital, Baylor College of Medicine	Houston	Texas
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	UCLA	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	Children's Hospital of Wisconsin-Milwaukee	Milwaukee	Wisconsin
United States	University of Minnesota Medical Center	Minneapolis	Minnesota
United States	Children's Hospital of New Orleans at LSUHSC	New Orleans	Louisiana
United States	Memorial Sloan-kettering Cancer Center	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	Phoenix Children's Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Mayo Clinic Hospital	Rochester	Minnesota
United States	University of Rochester Medical Center/ Golisano Children's Hospital	Rochester	New York
United States	Cardinal Glennon Children's Hospital/ St. Louis University	Saint Louis	Missouri
United States	Washington University/ St.Louis Children's Hospital	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital - St. Petersburg, FL	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/Texas Transplant Institute	San Antonio	Texas
United States	University of California (UCSF) Benioff Children's Hospital	San Francisco	California
United States	Seattle Children's Research Institute	Seattle	Washington
United States	New York Medical College, Maria Fareri Children's Hospital	Valhalla	New York
United States	Children's National Medical Center, Washington DC	Washington	District of Columbia
United States	Alfred I. duPont Hospital for Children/Nemours	Wilmington	Delaware

Sponsors (3)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Primary Immune Deficiency Treatment Consortium (PIDTC), Rare Diseases Clinical Research Network

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (9)

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

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

Marsh RA, Leiding JW, Logan BR, Griffith LM, Arnold DE, Haddad E, Falcone EL, Yin Z, Patel K, Arbuckle E, Bleesing JJ, Sullivan KE, Heimall J, Burroughs LM, Skoda-Smith S, Chandrakasan S, Yu LC, Oshrine BR, Cuvelier GDE, Thakar MS, Chen K, Teira P, Shenoy — 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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Death	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.	HCT to date of death, up to an expected average of 3 years
Secondary	Engraftment	Engraftment will be measures in whole blood using either fluorescent in situ hybridization (FISH) for sex chromosomes or short tandem repeat polymerase chain reaction (PCR) or (STRs) in whole blood.	an expected average of 3 years
Secondary	Quality of Life Measures	Age appropriate testing will be performed at the cross-sectional visit in patients surviving at least two years posttransplant: Pediatrics quality of life (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; Standard Form (SF)-36 (adult); Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT BMT) (adult)	an expected average of 3 years
Secondary	Infections	CGD or transplant-related and transplant-related infection	an expected average of 3 years
Secondary	Autoimmune or inflammatory complications	- For HCT subjects, inflammation (inflammatory complications) includes chronic graft-versus-host disease (GVHD)	an expected average of 3 years

External Links

•   National Institute of Allergy and Infectious Diseases (NIAID)
•   Primary Immune Deficiency Treatment Consortium (PIDTC)
•   Rare Diseases Clinical Research Network