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).

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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

Total of all reporting groups

The Lung Allocation Score (LAS) diagnosis group characterizes a person's lung disease into one of four groups: A, B, C, or D. Group A includes obstructive lung diseases like emphysema and chronic obstructive pulmonary disease. Group B includes pulmonary vascular diseases like hypertension. Group C includes cystic fibrosis and bronchiectasis. Group D includes restrictive diseases like pulmonary fibrosis.

This measure summarizes the cross-tabulation of donor and recipient gender (e.g., Female Donor and Male Recipient).

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.

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%

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.

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

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

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

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

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.

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.

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.

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

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.

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

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.

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.

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.

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.

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.

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.

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.

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

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.

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

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

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

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.