Clinical trial NCT02082353: Patients Treated for Chronic Granulomatous Disease (CGD) Since 1995
Official title: Analysis of Patients Treated for Chronic Granulomatous Disease Since January 1, 1995
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Granulomatous Disease, Chronic
Keywords: Granulomatous Disease, Chronic
Hematopoietic Stem Cell Transplantation (HSCT)
bone marrow transplant (BMT)
non-transplant
factors associated with best outcomes of transplant in CGD
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Rare Diseases Clinical Research Network
name: Primary Immune Deficiency Treatment Consortium (PIDTC)
First posted: 2014-03-10
Enrollment: 1480
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Institutions participating in Rare Diseases Clinical Research Network (RDCRN)

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.

Eligibility 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).

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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.
* 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).

Primary outcomes:
measure: Death
timeFrame: HCT to date of death, up to an expected average of 3 years
Secondary outcomes:
measure: Engraftment
timeFrame: an expected average of 3 years
measure: Quality of Life Measures
timeFrame: an expected average of 3 years
measure: Infections
timeFrame: an expected average of 3 years
measure: Autoimmune or inflammatory complications
timeFrame: an expected average of 3 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Palo Alto
country: United States
facility: Lucile Salter Packard Children's Hospital at Stanford
state: California
city: San Francisco
country: United States
facility: University of California (UCSF) Benioff Children's Hospital
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Wilmington
country: United States
facility: Alfred I. duPont Hospital for Children/Nemours
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center, Washington DC
state: District of Columbia
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital - St. Petersburg, FL
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta, Emory University
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: New Orleans
country: United States
facility: Children's Hospital of New Orleans at LSUHSC
state: Louisiana
city: Bethesda
country: United States
facility: NIH Clinical Center Genetic Immunotherapy Section
state: Maryland
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Hospital
state: Minnesota
city: Saint Louis
country: United States
facility: Cardinal Glennon Children's Hospital/ St. Louis University
state: Missouri
city: Saint Louis
country: United States
facility: Washington University/ St.Louis Children's Hospital
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan-kettering Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center/ Golisano Children's Hospital
state: New York
city: Valhalla
country: United States
facility: New York Medical College, Maria Fareri Children's Hospital
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies/ University Hospitals Case Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital, Baylor College of Medicine
state: Texas
city: San Antonio
country: United States
facility: Methodist Children's Hospital of South Texas/Texas Transplant Institute
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center/ University of Utah
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Research Institute
state: Washington
city: Madison
country: United States
facility: University of Wisconsin/ American Family Children's Hospital
state: Wisconsin
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin-Milwaukee
state: Wisconsin
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: Cancer Care Manitoba
state: Manitoba
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: CHU St. Justine
state: Quebec
Study officials:
affiliation: University of California, San Francisco
name: Jennifer M. Puck, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Los Angeles
name: Donald B. Kohn, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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, Fleisher TA, Bobby Gaspar H, Gungor T, Haddad E, Hovermale E, Huang F, Hurley A, Hurley M, Iyengar S, Kang EM, Logan BR, Long-Boyle JR, Malech HL, McGhee SA, Modell F, Modell V, Ochs HD, O'Reilly RJ, Parkman R, Rawlings DJ, Routes JM, Shearer WT, Small TN, Smith H, Sullivan KE, Szabolcs P, Thrasher A, Torgerson TR, Veys P, Weinberg K, Zuniga-Pflucker JC; workshop participants. Primary Immune Deficiency Treatment Consortium (PIDTC) report. J Allergy Clin Immunol. 2014 Feb;133(2):335-47. doi: 10.1016/j.jaci.2013.07.052. Epub 2013 Oct 15.
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. doi: 10.1016/j.jaci.2016.01.051. Epub 2016 Apr 22.
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, Gillio A, Davis J, Knutsen A, Smith AR, Moore TB, Schroeder ML, Goldman FD, Connelly JA, Porteus MH, Xiang Q, Shearer WT, Fleisher TA, Kohn DB, Puck JM, Notarangelo LD, Cowan MJ, O'Reilly RJ. Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med. 2014 Jul 31;371(5):434-46. doi: 10.1056/NEJMoa1401177.
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. No abstract available.
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, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience. J Allergy Clin Immunol. 2014 Apr;133(4):1092-8. doi: 10.1016/j.jaci.2013.09.044. Epub 2013 Nov 28.
citation: 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, Loechelt B, Moore T, Buckley RH. The natural history of children with severe combined immunodeficiency: baseline features of the first fifty patients of the primary immune deficiency treatment consortium prospective study 6901. J Clin Immunol. 2013 Oct;33(7):1156-64. doi: 10.1007/s10875-013-9917-y. Epub 2013 Jul 2.
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 deficiency diseases: recognition, diagnosis, and management. J Allergy Clin Immunol. 2009 Dec;124(6):1152-60.e12. doi: 10.1016/j.jaci.2009.10.022.
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 S, Phelan R, Forbes LR, Chellapandian D, Davila Saldana BJ, Shah AJ, Weinacht KG, Joshi A, Boulad F, Quigg TC, Dvorak CC, Grossman D, Torgerson T, Graham P, Prasad V, Knutsen A, Chong H, Miller H, de la Morena MT, DeSantes K, Cowan MJ, Notarangelo LD, Kohn DB, Stenger E, Pai SY, Routes JM, Puck JM, Kapoor N, Pulsipher MA, Malech HL, Parikh S, Kang EM; submitted on behalf of the Primary Immune Deficiency Treatment Consortium. Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT. J Clin Immunol. 2019 Oct;39(7):653-667. doi: 10.1007/s10875-019-00659-8. Epub 2019 Aug 2.