B Cell Induction in Pediatric Lung Transplantation

B Cell Targeted Induction to Improve Outcomes in Pediatric Lung Transplantation (CTOTC-08)

In this study, doctors are trying to see if a study drug called rituximab (Rituxan®) will lower the number of B cells in the body. Doctors are also trying to see if decreasing B cells with rituximab (Rituxan®) can prevent injury to the transplanted lung. This treatment has been studied in other types of solid organ transplants.

Patients who receive a lung transplant are at risk for rejection of the transplanted lung(s). Rejection occurs when the new lung triggers the body's defense (immune) system. When the immune system is triggered special cells are sent out to destroy the new lung and eventually the lung may not be able to function as it should. These special cells include B cells. B cells are an important part of the immune system and help the body fight infection. One way B cells fight infection is by producing antibodies. B cells and the antibodies they produce are involved in some kinds of rejection after organ transplantation.

Inclusion Criteria:

Enrollment:

1. Subject and/or parent guardian must be able to understand and provide informed consent;

2. Candidate for a primary lung transplant (listed for lung transplant);

3. Female and male subjects with reproductive potential must agree to use FDA approved methods of birth control for 12-months after completion of treatment.

4. Adequate bone marrow functions based on the following criteria:

   • Absolute neutrophil count (ANC): >1000mm^3
   • Platelets: >100,000/mm^3
   • Hemoglobin: >7 gm/dL
   • AST or ALT< 2x Upper Limit of Normal unless related to primary disease

Randomization:

Individuals who meet all of the following criteria are eligible for randomization:

1. Serum IgG immunoglobulin level greater than lower level of normal for age based on local laboratory ranges or 400mg/dL within 90 days prior to randomization;
2. Female subjects of childbearing potential must have a negative pregnancy test within 4 hours of transplant;
3. Negative for Hepatitis B infection (if at time of transplant, participant does not exhibit effective immunization, the participant should be re-tested).

Exclusion Criteria:

Enrollment:

Individuals who meet any of these criteria are not eligible for enrollment as study participants:

1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol;
2. Multi-organ transplant;
3. Previous treatment with rituximab (Rituxan®);
4. History of severe allergic anaphylactic reactions to humanized or murine monoclonal antibodies;
5. History of severe reaction to previous therapy with intravenous immunoglobulin (IVIG);
6. History of Burkholderia cenocepacia;
7. History of anti-CD20 therapy;
8. Persistent hypogammaglobulinemia (IgG < lower level of normal for age based on local laboratory ranges or 400 gm/dL for >2 months) and/or IVIG replacement therapy;
9. Positive blood culture, sepsis or other disease process with hemodynamic instability at time of enrollment;
10. Any history of serologic positivity to HIV, HBsAg, HBcAb and HCV Ab;
11. History of malignancy less than 2 years in remission of malignancy (any history of adequately treated in-situ cervical carcinoma, or adequately treated basal or squamous cell carcinoma of the skin will be permitted);
12. Any condition, including psychiatric disorders, that in the opinion of the investigator would interfere with the subject's ability to comply with study requirements;
13. Participation in another investigational trial within 4 weeks of enrollment;
14. Currently lactating or plans to become pregnant during the timeframe of the study follow-up period;
15. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.

Randomization:

Individuals who meet any of these criteria are not eligible for randomization:

1. Use of an induction agent other than Thymoglobulin®;
2. Renal insufficiency requiring hemodialysis or ultrafiltration;
3. Inability to obtain intravenous access;
4. Positive blood culture, sepsis or other disease process with hemodynamic instability at time of transplant;
5. Use of investigational agent(s) within 5 half-lives of the investigational drug or 4 weeks, whichever is longer;
6. Receipt of a MMR vaccine within 30 days prior to randomization;
7. Any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with study requirements.