B Cell Induction in Pediatric Lung Transplantation

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT02266888
• Collaborator: Clinical Trials in Organ Transplantation in Children (Other), Rho Federal Systems Division, Inc. (Industry)
• Enrollment: 45
• Locations: 7
• Arms: 2
• Actual Duration (Months): 53.2
• Patients Per Site: 6.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lung Transplant	Biological: Rituximab (Rituxan®); Biological: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: B Cell Targeted Induction to Improve Outcomes in Pediatric Lung Transplantation (CTOTC-08)
• Actual Study Start Date: Jan 22, 2015
• Actual Primary Completion Date: Jun 30, 2019
• Actual Study Completion Date: Jun 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rituximab Induction Rituximab (Rituxan®) Induction Therapy Plus Standard of Care Immunosuppression (thymoglobulin induction, tacrolimus or equivalent, mycophenolate mofetil (MMF) or equivalent, and steroids)	Biological: 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).; Other Names: Rituxan®
Placebo Comparator: Placebo Induction Placebo Induction Therapy Plus Standard of Care Immunosuppression (Thymoglobulin® induction, tacrolimus or equivalent, mycophenolate mofetil (MMF) or equivalent, and steroids)	Biological: Placebo; 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).

Outcome Measures

Primary Outcome Measures

1. Earliest Time to Any of the Following Events: Chronic Allograft Dysfunction, Listed for Retransplant or Death [Up to 35 months post-transplant]

   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.

Secondary Outcome Measures

1. Percent of Participants Diagnosed With Chronic Allograft Dysfunction [Up to 35 months post-transplant]

   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%

2. Percent of Participants Listed for Re-Transplant During the Study Follow-Up Period [Up to 35 months post-transplant]

   Participants with a reported date of listing for a second lung transplant during the study follow-up period.

3. Percent of Participants Who Died During the Study Follow-Up Period [Up to 35 months post-transplant]

   Participants with a reported date of death were considered to have met this outcome.

4. Percent of Participants With Primary Graft Dysfunction (PGD) [Up to 72 hours post-transplant]

   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.

5. Percent of Participants With Occurrence of Grade A Acute Rejection [Up to 24 months post-transplant]

   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.

6. Percent of Participants With Occurrence of Antibody Mediated Rejection [Up to 24 months post-transplant]

   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.

7. Percent of Participants Meeting Tacrolimus Variability Threshold [Up to 24 months post-transplant]

   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.

8. Percent of Participants Meeting Tacrolimus Variability Threshold Who Completed Tacrolimus Variability Intervention [Up to 27 months post-transplant]

   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.

9. Magnitude of Change in Standard Deviation of Tacrolimus Levels Following Intervention [Up to 19 months post-transplant]

   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.

10. Percent of Participants Experiencing an Infection Episode [Up to 24 months post-transplant]

    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.

11. Number of Participants With Severity of Infection Episodes [Up to 24 months post-transplant]

    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.

12. Percent of Participants Experiencing a Serious Adverse Event (SAE) Related to Rituximab [Up to 35 months post-transplant]

    The percentage of participants with Serious Adverse Events (SAEs) as determined by the trial's medical monitor to be related to rituximab is reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University	Palo Alto	California	United States	94305
2	Children's Hospital Boston	Boston	Massachusetts	United States	02115
3	Washington University	Saint Louis	Missouri	United States	63110
4	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
5	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
6	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
7	Texas Children's Hospital	Houston	Texas	United States	77030

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)
• Clinical Trials in Organ Transplantation in Children
• Rho Federal Systems Division, Inc.

Investigators

• Study Chair: Stuart Sweet, M.D., Ph.D., Washington University Medical Center: Department of Pediatrics, Division of Allergy, Immunology and Pulmonary Medicine
• Study Chair: Lara Danziger-Isakov, M.D., M.P.H., Cincinnati Children's Hospital: Division of Infectious Diseases

Study Documents (Full-Text)

• Study Protocol - Jul 16, 2018
• Statistical Analysis Plan - Sep 25, 2019

More Information

Additional Information:

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)
• Clinical Trials in Organ Transplantation in Children (CTOT-C)

Publications

None provided.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT02266888
• Other Study ID Numbers: DAIT CTOTC-08; NIAID CRMS ID#: 20181
• First Posted: Oct 17, 2014
• Last Update Posted: Oct 26, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): B cells; lung transplant recipient; rituximab; placebo; standard of care
• Additional relevant MeSH terms: Rituximab

Study Results

Participant Flow

Recruitment Details	Seven sites in the United States enrolled 45 participants into this trial.

Arm/Group Title	Rituximab	Placebo	Discontinued Pre-Transplant	Discontinued Pre-Randomization
Arm/Group Description	Induction: Rituximab was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.	Induction: Rituximab placebo was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.	Participants who enrolled, but withdrew from the study prior to receiving a transplant.	Participants who were enrolled and transplanted on study, but withdrew from the study prior to randomization.
Period Title: Overall Study
STARTED	15	12	11	7
COMPLETED	8	8	0	0
NOT COMPLETED	7	4	11	7

Baseline Characteristics

Arm/Group Title	Rituximab	Placebo	Total
Arm/Group Description	Induction: Rituximab was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.	Induction: Rituximab placebo was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.	Total of all reporting groups
Overall Participants	15	12	27
Age (Count of Participants)
<=18 years	15 100%	11 91.7%	26 96.3%
Between 18 and 65 years	0 0%	1 8.3%	1 3.7%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.5 (4.55)	13.2 (4.47)	12.8 (4.44)
Sex: Female, Male (Count of Participants)
Female	8 53.3%	6 50%	14 51.9%
Male	7 46.7%	6 50%	13 48.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 13.3%	3 25%	5 18.5%
Not Hispanic or Latino	10 66.7%	8 66.7%	18 66.7%
Unknown or Not Reported	3 20%	1 8.3%	4 14.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 6.7%	0 0%	1 3.7%
White	12 80%	10 83.3%	22 81.5%
More than one race	1 6.7%	0 0%	1 3.7%
Unknown or Not Reported	1 6.7%	2 16.7%	3 11.1%
Region of Enrollment (Count of Participants)
United States	15 100%	12 100%	27 100%
Pre-Transplant Lung Allocation Score (LAS) Diagnosis Group (Count of Participants)
Group A	1 6.7%	0 0%	1 3.7%
Group B	1 6.7%	0 0%	1 3.7%
Group C	8 53.3%	10 83.3%	18 66.7%
Group D	5 33.3%	2 16.7%	7 25.9%
Donor and Recipient Gender (Count of Participants)
Female Donor, Female Recipient	5 33.3%	3 25%	8 29.6%
Female Donor, Male Recipient	1 6.7%	0 0%	1 3.7%
Male Donor, Female Recipient	3 20%	3 25%	6 22.2%
Male Donor, Male Recipient	6 40%	6 50%	12 44.4%

Outcome Measures

1. Primary Outcome

Title	Earliest Time to Any of the Following Events: Chronic Allograft Dysfunction, Listed for Retransplant or Death
Description	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.
Time Frame	Up to 35 months post-transplant

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants who received at least a portion of the initial rituximab or placebo infusion.

Arm/Group Title	Rituximab	Placebo
Arm/Group Description	Induction: Rituximab was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.	Induction: Rituximab placebo was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.
Measure Participants	15	12
Median (90% Confidence Interval) [Days]	NA	703

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.514
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.673
	Confidence Interval	(2-Sided) 90%; 0.248 to 1.826
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio estimated for Rituximab vs. Placebo

2. Secondary Outcome

Title	Percent of Participants Diagnosed With Chronic Allograft Dysfunction
Description	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%
Time Frame	Up to 35 months post-transplant

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants who 1.) Received at least a portion of the initial rituximab or placebo infusion and 2.) Had at least one biopsy evaluable for OB and sufficient pulmonary function tests for evaluation of BOS.

Arm/Group Title	Rituximab	Placebo
Arm/Group Description	Induction: Rituximab was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.	Induction: Rituximab placebo was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.
Measure Participants	14	11
Number (90% Confidence Interval) [Percent of Participants]	28.6 190.7%	27.3 227.5%

3. Secondary Outcome

Title	Percent of Participants Listed for Re-Transplant During the Study Follow-Up Period
Description	Participants with a reported date of listing for a second lung transplant during the study follow-up period.
Time Frame	Up to 35 months post-transplant

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants who received at least a portion of the initial rituximab or placebo infusion.

Arm/Group Title	Rituximab	Placebo
Arm/Group Description	Induction: Rituximab was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.	Induction: Rituximab placebo was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.
Measure Participants	15	12
Number (90% Confidence Interval) [Percent of Participants]	0 0%	8.3 69.2%

4. Secondary Outcome

Title	Percent of Participants Who Died During the Study Follow-Up Period
Description	Participants with a reported date of death were considered to have met this outcome.
Time Frame	Up to 35 months post-transplant

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants who received at least a portion of the initial rituximab or placebo infusion.

Arm/Group Title	Rituximab	Placebo
Arm/Group Description	Induction: Rituximab was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.	Induction: Rituximab placebo was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.
Measure Participants	15	12
Number (90% Confidence Interval) [Percent of Participants]	13.3 88.7%	25.0 208.3%

5. Secondary Outcome

Title	Percent of Participants With Primary Graft Dysfunction (PGD)
Description	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.
Time Frame	Up to 72 hours post-transplant

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants who received at least a portion of the initial rituximab or placebo infusion and had available blood gas (e.g., arterial oxygen pressure) data during the first 72 hours post-transplant.

Arm/Group Title	Rituximab	Placebo
Arm/Group Description	Induction: Rituximab was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.	Induction: Rituximab placebo was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.
Measure Participants	12	7
Number (90% Confidence Interval) [Percent of Participants]	25.0 166.7%	14.3 119.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments
	Method	Fisher Exact
	Comments

6. Secondary Outcome

Title	Percent of Participants With Occurrence of Grade A Acute Rejection
Description	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.
Time Frame	Up to 24 months post-transplant

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants who received at least a portion of the initial rituximab or placebo infusion.

Arm/Group Title	Rituximab	Placebo
Arm/Group Description	Induction: Rituximab was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.	Induction: Rituximab placebo was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.
Measure Participants	15	12
Number (90% Confidence Interval) [Percent of Participants]	13.3 88.7%	16.7 139.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments
	Method	Fisher Exact
	Comments

7. Secondary Outcome

Title	Percent of Participants With Occurrence of Antibody Mediated Rejection
Description	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.
Time Frame	Up to 24 months post-transplant

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants who received at least a portion of the initial rituximab or placebo infusion.

Arm/Group Title	Rituximab	Placebo
Arm/Group Description	Induction: Rituximab was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.	Induction: Rituximab placebo was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.
Measure Participants	15	12
Number (90% Confidence Interval) [Percent of Participants]	0 0%	16.7 139.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.188
	Comments
	Method	Fisher Exact
	Comments

8. Secondary Outcome

Title	Percent of Participants Meeting Tacrolimus Variability Threshold
Description	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.
Time Frame	Up to 24 months post-transplant

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants who received at least a portion of the initial rituximab or placebo infusion and who had at least 3 outpatient tacrolimus trough levels collected that were at least 3 months post-transplant.

Arm/Group Title	Rituximab	Placebo
Arm/Group Description	Induction: Rituximab was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.	Induction: Rituximab placebo was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.
Measure Participants	15	11
Number (90% Confidence Interval) [Percent of Participants]	93.3 622%	100 833.3%

9. Secondary Outcome

Title	Percent of Participants Meeting Tacrolimus Variability Threshold Who Completed Tacrolimus Variability Intervention
Description	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.
Time Frame	Up to 27 months post-transplant

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants who received at least a portion of the initial rituximab or placebo infusion, which was subset to participants who qualified for and agreed to participate in the TVI.

Arm/Group Title	Rituximab	Placebo
Arm/Group Description	Induction: Rituximab was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.	Induction: Rituximab placebo was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.
Measure Participants	7	8
Number (90% Confidence Interval) [Percent of Participants]	85.7 571.3%	100 833.3%

10. Secondary Outcome

Title	Magnitude of Change in Standard Deviation of Tacrolimus Levels Following Intervention
Description	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.
Time Frame	Up to 19 months post-transplant

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants who received at least a portion of the initial rituximab or placebo infusion, which was subset to participants who qualified for and agreed to participate in the TVI and who had both a pre-TVI and post-TVI measurement available.

Arm/Group Title	Rituximab	Placebo
Arm/Group Description	Induction: Rituximab was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.	Induction: Rituximab placebo was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.
Measure Participants	7	7
Pre-TVI enrollment	3.95 (1.664)	5.18 (2.423)
180 Days after TVI enrollment	3.03 (0.948)	2.86 (1.636)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Placebo
	Comments	This is not a comparison between treatment groups, but rather a comparison between timepoints.The Rituximab and Placebo groups were combined for purposes of testing the hypothesis that there would be no change in SD between pre-enrollment and 180 days post-enrollment into the TVI.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments
	Method	Paired t-Test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.62
	Confidence Interval	(2-Sided) 90%; -2.64 to -0.60
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Percent of Participants Experiencing an Infection Episode
Description	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.
Time Frame	Up to 24 months post-transplant

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants who received at least a portion of the initial rituximab or placebo infusion.

Arm/Group Title	Rituximab	Placebo
Arm/Group Description	Induction: Rituximab was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.	Induction: Rituximab placebo was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.
Measure Participants	15	12
Number [Percent of Participants]	100 666.7%	100 833.3%

12. Secondary Outcome

Title	Number of Participants With Severity of Infection Episodes
Description	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.
Time Frame	Up to 24 months post-transplant

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants who received at least a portion of the initial rituximab or placebo infusion.

Arm/Group Title	Rituximab	Placebo
Arm/Group Description	Induction: Rituximab was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.	Induction: Rituximab placebo was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.
Measure Participants	15	12
Grade < 3 (Mild to Moderate)	4 26.7%	4 33.3%
Grade 3 (Severe)	8 53.3%	7 58.3%
Grade 4 (Life-threatening or Disabling)	1 6.7%	0 0%
Grade 5 (Fatal)	2 13.3%	1 8.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.502
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

13. Secondary Outcome

Title	Percent of Participants Experiencing a Serious Adverse Event (SAE) Related to Rituximab
Description	The percentage of participants with Serious Adverse Events (SAEs) as determined by the trial's medical monitor to be related to rituximab is reported.
Time Frame	Up to 35 months post-transplant

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants who received at least a portion of the initial rituximab or placebo infusion.

Arm/Group Title	Rituximab	Placebo
Arm/Group Description	Induction: Rituximab was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.	Induction: Rituximab placebo was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.
Measure Participants	15	12
Number (90% Confidence Interval) [Percent of Participants]	73.3 488.7%	58.3 485.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.448
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	Up to 35 months post-transplant
Adverse Event Reporting Description	Only adverse events grade 3 or higher were collected. Information was recorded by the site on the AE/SAE electronic Case Report Form (eCRF). All SAEs were to be reported within 24 hours of awareness, regardless of relationship to study procedures/therapy or expectedness of the event. SAEs included death, life-threatening events, hospitalization (or prolongation), inability to conduct normal life functions, birth defect, or condition requiring intervention to prevent these items.
Arm/Group Title	Rituximab		Placebo		Discontinued Pre-Transplant		Discontinued Pre-Randomization
Arm/Group Description	Induction: Rituximab was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.		Induction: Rituximab placebo was administered in two 375 mg/m^2 doses: on Day 0 within 12 hours of return to ICU following transplant and on Day 12 (+/-2 days). Standard of care immunosuppression (thymoglobulin induction, tacrolimus or equivalent, MMF or equivalent, and steroids) was also utilized at each site.		Subjects who enrolled, but withdrew from the study prior to receiving a transplant.		Subjects who were enrolled and transplanted on study, but withdrew from the study prior to randomization.
All Cause Mortality
	Rituximab		Placebo		Discontinued Pre-Transplant		Discontinued Pre-Randomization
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/15 (13.3%)		3/12 (25%)		4/11 (36.4%)		2/7 (28.6%)
Serious Adverse Events
	Rituximab		Placebo		Discontinued Pre-Transplant		Discontinued Pre-Randomization
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/15 (86.7%)		9/12 (75%)		3/11 (27.3%)		3/7 (42.9%)
Blood and lymphatic system disorders
Anaemia	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Febrile neutropenia	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Cardiac disorders
Atrial tachycardia	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Cardiac arrest	0/15 (0%)	0	0/12 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Constipation	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Distal ileal obstruction syndrome	0/15 (0%)	0	1/12 (8.3%)	2	0/11 (0%)	0	0/7 (0%)	0
Distal intestinal obstruction syndrome	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Gastrooesophageal reflux disease	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Intestinal obstruction	1/15 (6.7%)	1	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Vomiting	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Hepatobiliary disorders
Cholecystitis	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Immune system disorders
Transplant rejection	2/15 (13.3%)	2	3/12 (25%)	3	0/11 (0%)	0	0/7 (0%)	0
Infections and infestations
Arthritis bacterial	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Arthritis infective	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Bacterial infection	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Bronchitis	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Chronic sinusitis	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Corona virus infection	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Gastroenteritis	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Lower respiratory tract infection	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Nocardiosis	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Pharyngitis	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Pneumonia	4/15 (26.7%)	5	4/12 (33.3%)	5	0/11 (0%)	0	0/7 (0%)	0
Pneumonia bacterial	1/15 (6.7%)	1	1/12 (8.3%)	2	0/11 (0%)	0	0/7 (0%)	0
Pseudomonas infection	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Respiratory syncytial virus infection	2/15 (13.3%)	2	2/12 (16.7%)	2	0/11 (0%)	0	0/7 (0%)	0
Respiratory tract infection	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Rhinovirus infection	1/15 (6.7%)	1	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Septic shock	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Sinusitis	1/15 (6.7%)	1	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Upper respiratory tract infection	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Urinary tract infection	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Wound infection	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Injury, poisoning and procedural complications
Complications of transplant surgery	0/15 (0%)	0	0/12 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0
Post procedural haemorrhage	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Procedural haemorrhage	0/15 (0%)	0	0/12 (0%)	0	0/11 (0%)	0	3/7 (42.9%)	3
Transplant dysfunction	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Investigations
Blood glucose increased	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Lymphocyte count decreased	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Hyperglycaemia	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Hyperkalaemia	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Musculoskeletal and connective tissue disorders
Synovitis	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Nervous system disorders
Convulsion	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Posterior reversible encephalopathy syndrome	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Renal and urinary disorders
Renal failure acute	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Respiratory, thoracic and mediastinal disorders
Aspiration	1/15 (6.7%)	1	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Choking	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Chylothorax	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Diaphragmatic paralysis	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Hypoxia	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Obliterative bronchiolitis	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Pneumonitis	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Pneumothorax	4/15 (26.7%)	5	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Pulmonary haemorrhage	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Respiratory failure	0/15 (0%)	0	0/12 (0%)	0	1/11 (9.1%)	1	0/7 (0%)	0
Surgical and medical procedures
Thoracic cavity drainage	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Other (Not Including Serious) Adverse Events
	Rituximab		Placebo		Discontinued Pre-Transplant		Discontinued Pre-Randomization
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/15 (40%)		4/12 (33.3%)		0/11 (0%)		0/7 (0%)
Blood and lymphatic system disorders
Febrile neutropenia	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Gastrointestinal disorders
Diarrhoea	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Ileus	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
General disorders
Fatigue	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Influenza like illness	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Immune system disorders
Transplant rejection	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Infections and infestations
Clostridium difficile infection	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Gastroenteritis clostridial	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Otitis media	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Pneumonia	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Sexually transmitted disease	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Tracheitis	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Injury, poisoning and procedural complications
Procedural haemorrhage	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0
Investigations
Lymphocyte count decreased	2/15 (13.3%)	2	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Nervous system disorders
Convulsion	0/15 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/7 (0%)	0
Headache	1/15 (6.7%)	1	0/12 (0%)	0	0/11 (0%)	0	0/7 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.