B Cell Induction in Pediatric Lung Transplantation

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Lung Transplant

Intervention / Treatment
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* Biological: Rituximab (Rituxan®)
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Enrollment: Subject and/or parent guardian must be able to understand and provide informed consent; Candidate for a primary lung transplant (listed for lung transplant); Female and male subjects with reproductive potential must agree to use FDA approved methods of birth control for 12-months after completion of treatment. 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: 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; Female subjects of childbearing potential must have a negative pregnancy test within 4 hours of transplant; 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: Inability or unwillingness of a participant to give written informed consent or comply with study protocol; Multi-organ transplant; Previous treatment with rituximab (Rituxan®); History of severe allergic anaphylactic reactions to humanized or murine monoclonal antibodies; History of severe reaction to previous therapy with intravenous immunoglobulin (IVIG); History of Burkholderia cenocepacia; History of anti-CD20 therapy; 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; Positive blood culture, sepsis or other disease process with hemodynamic instability at time of enrollment; Any history of serologic positivity to HIV, HBsAg, HBcAb and HCV Ab; 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); Any condition, including psychiatric disorders, that in the opinion of the investigator would interfere with the subject's ability to comply with study requirements; Participation in another investigational trial within 4 weeks of enrollment; Currently lactating or plans to become pregnant during the timeframe of the study follow-up period; 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: Use of an induction agent other than Thymoglobulin®; Renal insufficiency requiring hemodialysis or ultrafiltration; Inability to obtain intravenous access; Positive blood culture, sepsis or other disease process with hemodynamic instability at time of transplant; Use of investigational agent(s) within 5 half-lives of the investigational drug or 4 weeks, whichever is longer; Receipt of a MMR vaccine within 30 days prior to randomization; Any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with study requirements.

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab Induction<br>Rituximab (Rituxan®) Induction Therapy Plus Standard of Care Immunosuppression (thymoglobulin induction, tacrolimus or equivalent, mycophenolate mofetil (MMF) or equivalent, and steroids) | Biological: Rituximab (Rituxan®)<br>* 2 Doses: 375 mg/m^2 on Day 0 (within 12 hours of return to ICU following transplant) and Day 12 (+/-2 days).<br>* Other names: Rituxan®;|
| Placebo Comparator: Placebo Induction<br>Placebo Induction Therapy Plus Standard of Care Immunosuppression (Thymoglobulin® induction, tacrolimus or equivalent, mycophenolate mofetil (MMF) or equivalent, and steroids) | Biological: Placebo<br>* Placebo for Rituximab (Rituxan®). 2 Doses: 375 mg/m^2 on Day 0 (within 12 hours of return to ICU following transplant) and Day 12 (+/-2 days).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Earliest Time to Any of the Following Events: Chronic Allograft Dysfunction, Listed for Retransplant or Death | This composite outcome measures is defined as the earliest time post-transplant to any of the following events during the follow-up period: Chronic Allograft Dysfunction (defined as the occurrence of confirmed Bronchiolitis Obliterans Syndrome (BOS) grade 0-p or higher or a diagnosis of Obliterative Bronchiolitis (OB)), Listed for re-transplant (e.g., second lung transplant), or Death. | Up to 35 months post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants Diagnosed With Chronic Allograft Dysfunction | Chronic allograft dysfunction is defined as Bronchiolitis Obliterans Syndrome (BOS) ≥Grade 0p according to the International Society for Heart and Lung Transplantation (ISHLT) criteria, or biopsy proven histologic evidence of obliterans bronchiolitis. BOS is an indicator of post-transplant loss of lung function, a sign of allograft dysfunction that presents as a persistent decline in forced expiratory volume in 1 second (FEV1) or forced expiratory flow (FEF) 25-75% (often accompanied by evidence of airway obstruction) that is not the result of other causes such as acute rejection, acute infection, and/or airway stenosis. BOS grade: Spirometry % of baseline 0: FEV1 >90% and FEF25-75% >75% 0-p: FEV1 81-90% and FEF25-75% ≤75% 1: FEV1 66-80% 2: FEV1 51-65% 3: FEV1 ≤50% | Up to 35 months post-transplant | 
| Percent of Participants Listed for Re-Transplant During the Study Follow-Up Period | Participants with a reported date of listing for a second lung transplant during the study follow-up period. | Up to 35 months post-transplant | 
| Percent of Participants Who Died During the Study Follow-Up Period | Participants with a reported date of death were considered to have met this outcome. | Up to 35 months post-transplant | 
| Percent of Participants With Primary Graft Dysfunction (PGD) | The International Society for Heart and Lung Transplantation's (ISHLT) grading for Primary Graft Dysfunction (PGD) was used. The severity of PGD is graded 0 - 3 based on the presence or absence of diffuse opacities on chest radiograph and the ratio of arterial oxygen pressure to inspired oxygen concentration. The grading system predicts post-lung transplant outcomes with Grade 3 being the worse. Participants were classified as having PGD if graded as 2 or 3 at any time during the first 72 hours post-transplant. | Up to 72 hours post-transplant | 
| Percent of Participants With Occurrence of Grade A Acute Rejection | Pulmonary allograft rejection was defined according to the 2007 International Society for Heart and Lung Transplantation's (ISHLT). Each transbronchial biopsy (TBBx) was evaluated by the local center's pathologist and graded as described below. Acute Cellular Rejection (ACR) Grade Classification: A0: None A1: Minimal A2: Mild A3: Moderate A4: Severe Participants met this outcome if at any point in time their biopsy was classified as A2, A3, or A4. | Up to 24 months post-transplant | 
| Percent of Participants With Occurrence of Antibody Mediated Rejection | Antibody Mediated Rejection (AMR) was defined based on the revision of the 1996 Working Formulation for the Standardization of Nomenclature in the Diagnosis of Lung Rejection, the Pathology of pulmonary AMR and the 2012 update from the Pathology Council of the International Society for Heart and Lung Transplantation (ISHLT). AMR was diagnosed locally and graded as: Grade I: Latent humoral response - Donor Specific Antibody (DSA) or autoantibody present and absence of both abnormal histology and unexplained graft dysfunction Grade II: Subclinical humoral rejection - DSA or autoantibody present and abnormal histology present with an absence of unexplained graft dysfunction Grade III: Humoral rejection - DSA or autoantibody present and abnormal histology present and unexplained graft dysfunction present. Higher grades indicate more severe AMR. Participants were considered to have met this outcome if at any point in time their biopsy was classified as Grade II or III. | Up to 24 months post-transplant | 
| Percent of Participants Meeting Tacrolimus Variability Threshold | Tacrolimus trough levels are generally collected post-transplant to allow clinicians to monitor transplant recipients' adherence to prescribed tacrolimus dosing. This outcome was designed for research purposes as an indicator of adherence to tacrolimus over time. Beginning at 3 months post-transplant, a rolling standard deviation (SD) was estimated for each participant who had at least 3 outpatient trough levels collected and recorded. The estimated SD could derive from up to 1 year worth of trough levels at any given time. The larger the SD (variation) of tacrolimus levels, the greater the nonadherence of participant(s) taking tacrolimus as prescribed. Nonadherence is a major reason for post-transplant morbidity. Participants were considered to have met this outcome, the tacrolimus variability threshold, if their estimated SD of tacrolimus medication levels at any time was 2.0 ng/mL or greater. | Up to 24 months post-transplant | 
| Percent of Participants Meeting Tacrolimus Variability Threshold Who Completed Tacrolimus Variability Intervention | For participants who met the Tacrolimus Variability Threshold and agreed to participate in the Tacrolimus Variability Intervention (TVI), a series of calls with the participant, parent(s)/guardian(s), and trained call center personnel were conducted to address barriers to adherence. Refer to Outcome Measure 8 for a description of tacrolimus variability threshold methodology. | Up to 27 months post-transplant | 
| Magnitude of Change in Standard Deviation of Tacrolimus Levels Following Intervention | Standard deviation (SD) is a number that describes how a group of measurements are spread out around the average value for that group. A low SD value means the numbers are close to the average; a high SD means the numbers are more spread out. The change in SD of tacrolimus levels was calculated by subtracting each participant's pre-intervention SD from their SD 180 days after enrollment into the intervention (i.e., value of SD 180 days after enrollment minus value of SD before enrollment). A change less than zero (i.e., a negative number) would indicate a decrease in SD, which is good, possibly as a result of the intervention. | Up to 19 months post-transplant | 
| Percent of Participants Experiencing an Infection Episode | Defined by: A local report of bacterial, fungal, or viral infection through either the organism specific case report form (CRF) or adverse event reporting; or Presence of symptoms at the time of a study visit without a local report of infection but with a corresponding Core Lab identified viral infection All symptoms reported at the time of a study visit were evaluated for any Epstein-Barr Virus (EBV) and Cytomegalovirus (CMV) infections identified by the Core Lab For any other infections identified in Core Lab Nasopharyngeal (NP) and Bronchoalveolar Lavage (BAL) biospecimens: shortness of breath, new x-ray or other imaging finding, new supplemental oxygen requirement, cough with sputum, and decreased spirometry were evaluated signs/symptoms. Participants were considered to have met this outcome if at any point in time they had an infection meeting the referenced criteria. | Up to 24 months post-transplant | 
| Number of Participants With Severity of Infection Episodes | The severity of infection episodes was determined by the site Principal Investigator (PI) using the adverse event (AE) scale of mild to moderate (Grade <3), severe (Grade 3), life-threatening (Grade 4), or fatal (Grade 5). Since the protocol restricted AE reporting to only those events which met National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 grading criteria of Grade 3 (moderate) or higher, any infection not reported as an AE was assigned a severity of Grade <3 (effectively combining Grades 1 and 2); all other infections utilized the assigned CTCAE severity grade of the corresponding AE. A higher severity grade indicates a more severe event. | Up to 24 months post-transplant | 
| Percent of Participants Experiencing a Serious Adverse Event (SAE) Related to Rituximab | The percentage of participants with Serious Adverse Events (SAEs) as determined by the trial's medical monitor to be related to rituximab is reported. | Up to 35 months post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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B cells, lung transplant recipient, rituximab, placebo, standard of care