Clinical trial NCT02266888: B Cell Induction in Pediatric Lung Transplantation
Official title: B Cell Targeted Induction to Improve Outcomes in Pediatric Lung Transplantation (CTOTC-08)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lung Transplant
Keywords: B cells
lung transplant recipient
rituximab
placebo
standard of care
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Clinical Trials in Organ Transplantation in Children
name: Rho Federal Systems Division, Inc.
First posted: 2014-10-17
Enrollment: 45
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Earliest Time to Any of the Following Events: Chronic Allograft Dysfunction, Listed for Retransplant or Death
timeFrame: Up to 35 months post-transplant
Secondary outcomes:
measure: Percent of Participants Diagnosed With Chronic Allograft Dysfunction
timeFrame: Up to 35 months post-transplant
measure: Percent of Participants Listed for Re-Transplant During the Study Follow-Up Period
timeFrame: Up to 35 months post-transplant
measure: Percent of Participants Who Died During the Study Follow-Up Period
timeFrame: Up to 35 months post-transplant
measure: Percent of Participants With Primary Graft Dysfunction (PGD)
timeFrame: Up to 72 hours post-transplant
measure: Percent of Participants With Occurrence of Grade A Acute Rejection
timeFrame: Up to 24 months post-transplant
measure: Percent of Participants With Occurrence of Antibody Mediated Rejection
timeFrame: Up to 24 months post-transplant
measure: Percent of Participants Meeting Tacrolimus Variability Threshold
timeFrame: Up to 24 months post-transplant
measure: Percent of Participants Meeting Tacrolimus Variability Threshold Who Completed Tacrolimus Variability Intervention
timeFrame: Up to 27 months post-transplant
measure: Magnitude of Change in Standard Deviation of Tacrolimus Levels Following Intervention
timeFrame: Up to 19 months post-transplant
measure: Percent of Participants Experiencing an Infection Episode
timeFrame: Up to 24 months post-transplant
measure: Number of Participants With Severity of Infection Episodes
timeFrame: Up to 24 months post-transplant
measure: Percent of Participants Experiencing a Serious Adverse Event (SAE) Related to Rituximab
timeFrame: Up to 35 months post-transplant
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
Study officials:
affiliation: Washington University Medical Center: Department of Pediatrics, Division of Allergy, Immunology and Pulmonary Medicine
name: Stuart Sweet, M.D., Ph.D.
role: STUDY_CHAIR
affiliation: Cincinnati Children's Hospital: Division of Infectious Diseases
name: Lara Danziger-Isakov, M.D., M.P.H.
role: STUDY_CHAIR
References:
citation: Sweet SC, Armstrong B, Blatter J, Chin H, Conrad C, Goldfarb S, Hayes D Jr, Heeger PS, Lyou V, Melicoff-Portillo E, Mohanakumar T, Odim J, Ravichandran R, Schecter M, Storch GA, Visner G, Williams NM, Danziger-Isakov L. CTOTC-08: A multicenter randomized controlled trial of rituximab induction to reduce antibody development and improve outcomes in pediatric lung transplant recipients. Am J Transplant. 2022 Jan;22(1):230-244. doi: 10.1111/ajt.16862. Epub 2021 Nov 5.
citation: Duncan-Park S, Dunphy C, Becker J, D'Urso C, Annunziato R, Blatter J, Conrad C, Goldfarb SB, Hayes D Jr, Melicoff E, Schecter M, Visner G, Armstrong B, Chin H, Kesler K, Williams NM, Odim JN, Sweet SC, Danziger-Isakov L, Shemesh E. Remote intervention engagement and outcomes in the Clinical Trials in Organ Transplantation in Children consortium multisite trial. Am J Transplant. 2021 Sep;21(9):3112-3122. doi: 10.1111/ajt.16567. Epub 2021 Apr 12.