Study Comparing Efficacy and Safety of Defibrotide vs Best Supportive Care in the Prevention of Hepatic Veno-Occlusive Disease in Adult and Pediatric Patients

VOD-free survival is a composite of survival status and VOD occurrence as determined by modified Seattle criteria adjudicated by a blinded independent EPAC. An event is defined as a VOD diagnosis (as assessed by the EPAC) or death, whichever, is earlier, up to and including Day +30 post-HSCT. The values reported below are participants who did not experience VOD or death by Day +30 post-HSCT.

Time frame: Day +30 Post-HSCT

Population: VOD-free survival was assessed using the Intent-to-Treat Analysis Set.

AUClast is the area under the defibrotide concentration-time curve from 0 (pre-dose) to time of last quantifiable defibrotide concentration at time t. AUClast is a summary statistic and it is not reported on an hourly basis. If veno-occlusive disease (VOD) occurs, the prophylaxis phase starts on the baseline date and ends on the day before the start date of rescue defibrotide. If VOD does not occur, the prophylaxis phase starts on the baseline date and ends on the date of study completion/early termination.

Time frame: Day +1 and +7 Post-HSCT

Population: AUClast was assessed using the Pharmacokinetic (PK) Evaluable Analysis Set. Intensive PK samples were collected during the prophylaxis phase on Day +1 and Day +7 post-HSCT in a subgroup of participants in the DP arm who separately consented for this sampling. Sparse PK samples were collected from participants throughout the study according to the protocol.

AUClast is the area under the defibrotide concentration-time curve from 0 (pre-dose) to time of last quantifiable defibrotide concentration at time t. AUClast is a summary statistic and it is not reported on an hourly basis. For the subset of participants who developed veno-occlusive disease (VOD) and received rescue defibrotide, the rescue treatment phase begins on the start date of rescue defibrotide and ends on the date of study completion/early termination.

Time frame: Day +14 Post-VOD Treatment

Population: AUClast was assessed using the Pharmacokinetic (PK) Evaluable Analysis Set. Frequent PK samples were collected from participants who developed VOD and received defibrotide rescue treatment (rescue phase) on VOD treatment Day 14. Sparse PK samples were collected from participants throughout the study according to the protocol.

For each of the five dimensions of mobility, self-care, activity, pain, and anxiety based on the descriptive system of the EQ-5D-5L, the numbers and percentages of participants for all categories (the three levels of reported problems and question not completed) at Day +180 Post-HSCT was assessed. Each dimension was categorized as follows: Condition improved, if the reported level of problem is lower at the assessment than baseline; condition unchanged, if the reported level of problem remains the same; condition deteriorated, if the reported level of problem is higher at that assessment than at baseline; and unknown, if the reported level of problem is missing either at baseline or at that assessment.

Time frame: Day +180 Post-HSCT

Population: EQ-5D-5L Activity was assessed using the Age ≥ 16 Years Safety Analysis Set.

For each of the five dimensions of mobility, self-care, activity, pain, and anxiety based on the descriptive system of the EQ-5D-5L, the numbers and percentages of participants for all categories (the three levels of reported problems and question not completed) at Day +180 Post-HSCT was assessed. Each dimension was categorized as follows: Condition improved, if the reported level of problem is lower at the assessment than baseline; condition unchanged, if the reported level of problem remains the same; condition deteriorated, if the reported level of problem is higher at that assessment than at baseline; and unknown, if the reported level of problem is missing either at baseline or at that assessment.

Time frame: Day +180 Post-HSCT

Population: EQ-5D-5L Anxiety was assessed using the Age ≥ 16 Years Safety Analysis Set.

For each of the five dimensions of mobility, self-care, activity, pain, and anxiety based on the descriptive system of the EQ-5D-5L, the numbers and percentages of participants for all categories (the three levels of reported problems and question not completed) at Day +180 Post-HSCT was assessed. Each dimension was categorized as follows: Condition improved, if the reported level of problem is lower at the assessment than baseline; condition unchanged, if the reported level of problem remains the same; condition deteriorated, if the reported level of problem is higher at that assessment than at baseline; and unknown, if the reported level of problem is missing either at baseline or at that assessment.

Time frame: Day +180 Post-HSCT

Population: EQ-5D-5L Mobility was assessed using the Age ≥ 16 Years Safety Analysis Set.

For each of the five dimensions of mobility, self-care, activity, pain, and anxiety based on the descriptive system of the EQ-5D-5L, the numbers and percentages of participants for all categories (the three levels of reported problems and question not completed) at Day +180 Post-HSCT was assessed. Each dimension was categorized as follows: Condition improved, if the reported level of problem is lower at the assessment than baseline; condition unchanged, if the reported level of problem remains the same; condition deteriorated, if the reported level of problem is higher at that assessment than at baseline; and unknown, if the reported level of problem is missing either at baseline or at that assessment.

Time frame: Day +180 Post-HSCT

Population: EQ-5D-5L Pain was assessed using the Age ≥ 16 Years Safety Analysis Set.

For each of the five dimensions of mobility, self-care, activity, pain, and anxiety based on the descriptive system of the EQ-5D-5L, the numbers and percentages of participants for all categories (the three levels of reported problems and question not completed) at Day +180 Post-HSCT was assessed. Each dimension was categorized as follows: Condition improved, if the reported level of problem is lower at the assessment than baseline; condition unchanged, if the reported level of problem remains the same; condition deteriorated, if the reported level of problem is higher at that assessment than at baseline; and unknown, if the reported level of problem is missing either at baseline or at that assessment.

Time frame: Day +180 Post-HSCT

Population: EQ-5D-5L Self-Care was assessed using the Age ≥ 16 Years Safety Analysis Set.

For each of the five dimensions of mobility, self-care, activity, pain, and anxiety based on the descriptive system of the EQ-5D-Y, self-report version, the numbers and percentages of participants for all categories (the three levels of reported problems and question not completed) at Day +180 post-HSCT was assessed. Each dimension was categorized as follows: Condition improved, if the reported level of problem is lower at the assessment than baseline; condition unchanged, if the reported level of problem remains the same; condition deteriorated, if the reported level of problem is higher at that assessment than at baseline; and unknown, if the reported level of problem is missing either at baseline or at that assessment.

Time frame: Day +180 Post-HSCT

Population: EQ-5D-Y Activity was assessed using the Age ≥ 4 and ≤ 7 Years Safety Analysis Set.

For each of the five dimensions of mobility, self-care, activity, pain, and anxiety based on the descriptive system of the EQ-5D-Y, self-report version, the numbers and percentages of participants for all categories (the three levels of reported problems and question not completed) at Day +180 post-HSCT was assessed. Each dimension was categorized as follows: Condition improved, if the reported level of problem is lower at the assessment than baseline; condition unchanged, if the reported level of problem remains the same; condition deteriorated, if the reported level of problem is higher at that assessment than at baseline; and unknown, if the reported level of problem is missing either at baseline or at that assessment.

Time frame: Day +180 Post-HSCT

Population: EQ-5D-Y Anxiety was assessed using the Age ≥ 4 and ≤ 7 Years Safety Analysis Set.

For each of the five dimensions of mobility, self-care, activity, pain, and anxiety based on the descriptive system of the EQ-5D-Y, self-report version, the numbers and percentages of participants for all categories (the three levels of reported problems and question not completed) at Day +180 post-HSCT was assessed. Each dimension was categorized as follows: Condition improved, if the reported level of problem is lower at the assessment than baseline; condition unchanged, if the reported level of problem remains the same; condition deteriorated, if the reported level of problem is higher at that assessment than at baseline; and unknown, if the reported level of problem is missing either at baseline or at that assessment.

Time frame: Day +180 Post-HSCT

Population: EQ-5D-Y Mobility was assessed using the Age ≥ 4 and ≤ 7 Years Safety Analysis Set.

For each of the five dimensions of mobility, self-care, activity, pain, and anxiety based on the descriptive system of the EQ-5D-Y, self-report version, the numbers and percentages of participants for all categories (the three levels of reported problems and question not completed) at Day +180 post-HSCT was assessed. Each dimension was categorized as follows: Condition improved, if the reported level of problem is lower at the assessment than baseline; condition unchanged, if the reported level of problem remains the same; condition deteriorated, if the reported level of problem is higher at that assessment than at baseline; and unknown, if the reported level of problem is missing either at baseline or at that assessment.

Time frame: Day +180 Post-HSCT

Population: EQ-5D-Y Pain was assessed using the Age ≥ 4 and ≤ 7 Years Safety Analysis Set.

For each of the five dimensions of mobility, self-care, activity, pain, and anxiety based on the descriptive system of the EQ-5D-Y, self-report version, the numbers and percentages of participants for all categories (the three levels of reported problems and question not completed) at Day +180 post-HSCT was assessed. Each dimension was categorized as follows: Condition improved, if the reported level of problem is lower at the assessment than baseline; condition unchanged, if the reported level of problem remains the same; condition deteriorated, if the reported level of problem is higher at that assessment than at baseline; and unknown, if the reported level of problem is missing either at baseline or at that assessment.

Time frame: Day +180 Post-HSCT

Population: EQ-5D-Y Self-Care was assessed using the Age ≥ 4 and ≤ 7 Years Safety Analysis Set.

For each of the five dimensions of mobility, self-care, activity, pain, and anxiety based on the descriptive system of the EQ-5D-Y, self-report version, the numbers and percentages of participants for all categories (the three levels of reported problems and question not completed) at Day +180 post-HSCT was assessed. Each dimension was categorized as follows: Condition improved, if the reported level of problem is lower at the assessment than baseline; condition unchanged, if the reported level of problem remains the same; condition deteriorated, if the reported level of problem is higher at that assessment than at baseline; and unknown, if the reported level of problem is missing either at baseline or at that assessment.

Time frame: Day +180 Post-HSCT

Population: EQ-5D-Y Activity at Day +180 post-HSCT was assessed using participants Age ≥ 8 and ≤ 15 Years Safety Analysis Set.

For each of the five dimensions of mobility, self-care, activity, pain, and anxiety based on the descriptive system of the EQ-5D-Y, self-report version, the numbers and percentages of participants for all categories (the three levels of reported problems and question not completed) at Day +180 post-HSCT was assessed. Each dimension was categorized as follows: Condition improved, if the reported level of problem is lower at the assessment than baseline; condition unchanged, if the reported level of problem remains the same; condition deteriorated, if the reported level of problem is higher at that assessment than at baseline; and unknown, if the reported level of problem is missing either at baseline or at that assessment.

Time frame: Day +180 Post-HSCT

Population: EQ-5D-Y Pain at Day +180 post-HSCT was assessed using participants Age ≥ 8 and ≤ 15 Years Safety Analysis Set.

For each of the five dimensions of mobility, self-care, activity, pain, and anxiety based on the descriptive system of the EQ-5D-Y, self-report version, the numbers and percentages of participants for all categories (the three levels of reported problems and question not completed) at Day +180 post-HSCT was assessed. Each dimension was categorized as follows: Condition improved, if the reported level of problem is lower at the assessment than baseline; condition unchanged, if the reported level of problem remains the same; condition deteriorated, if the reported level of problem is higher at that assessment than at baseline; and unknown, if the reported level of problem is missing either at baseline or at that assessment.

Time frame: Day +180 Post-HSCT

Population: EQ-5D-Y Mobility at Day +180 post-HSCT was assessed using participants Age ≥ 8 and ≤ 15 Years Safety Analysis Set.

For each of the five dimensions of mobility, self-care, activity, pain, and anxiety based on the descriptive system of the EQ-5D-Y, self-report version, the numbers and percentages of participants for all categories (the three levels of reported problems and question not completed) at Day +180 post-HSCT was assessed. Each dimension was categorized as follows: Condition improved, if the reported level of problem is lower at the assessment than baseline; condition unchanged, if the reported level of problem remains the same; condition deteriorated, if the reported level of problem is higher at that assessment than at baseline; and unknown, if the reported level of problem is missing either at baseline or at that assessment.

Time frame: Day +180 Post-HSCT

Population: EQ-5D-Y Pain at Day +180 post-HSCT was assessed using participants Age ≥ 8 and ≤ 15 Years Safety Analysis Set.

For each of the five dimensions of mobility, self-care, activity, pain, and anxiety based on the descriptive system of the EQ-5D-Y, self-report version, the numbers and percentages of participants for all categories (the three levels of reported problems and question not completed) at Day +180 post-HSCT was assessed. Each dimension was categorized as follows: Condition improved, if the reported level of problem is lower at the assessment than baseline; condition unchanged, if the reported level of problem remains the same; condition deteriorated, if the reported level of problem is higher at that assessment than at baseline; and unknown, if the reported level of problem is missing either at baseline or at that assessment.

Time frame: Day +180 Post-HSCT

Population: EQ-5D-Y Self-Care at Day +180 post-HSCT was assessed using participants Age ≥ 8 and ≤ 15 Years Safety Analysis Set.

Cmax is the maximum defibrotide plasma concentration, obtained directly from the observed data. Cmax is a summary statistic and it is not reported on an hourly basis. If veno-occlusive disease (VOD) occurs, the prophylaxis phase starts on the baseline date and ends on the day before the start date of rescue defibrotide. If VOD does not occur, the prophylaxis phase starts on the baseline date and ends on the date of study completion/early termination.

Time frame: Day +1 and +7 Post-HSCT

Population: Cmax was assessed using the Pharmacokinetic (PK) Evaluable Analysis Set. Intensive PK samples were collected during the prophylaxis phase on Day +1 and Day +7 post-HSCT in a subgroup of participants in the DP arm who separately consented for this sampling. Sparse PK samples were collected from participants throughout the study according to the protocol.

Cmax is the maximum defibrotide plasma concentration, obtained directly from the observed data. Cmax is a summary statistic and it is not reported on an hourly basis. For the subset of participants who developed veno-occlusive disease (VOD) and received rescue defibrotide, the rescue treatment phase begins on the start date of rescue defibrotide and ends on the date of study completion/early termination.

Time frame: Day +14 Post-VOD Treatment

Population: Cmax was assessed using the Pharmacokinetic (PK) Evaluable Analysis Set. Frequent PK samples were collected from participants who developed VOD and received defibrotide rescue treatment (rescue phase) on VOD treatment Day 14. Sparse PK samples were collected from participants throughout the study according to the protocol.

Mean systemic clearance after intravenous dosing. Mean clearance is a summary statistic and it is not reported on an hourly basis. If veno-occlusive disease (VOD) occurs, the prophylaxis phase starts on the baseline date and ends on the day before the start date of rescue defibrotide. If VOD does not occur, the prophylaxis phase starts on the baseline date and ends on the date of study completion/early termination.

Time frame: Day +1 and +7 Post-HSCT

Population: Mean clearance was assessed using the Pharmacokinetic (PK) Evaluable Analysis Set. Intensive PK samples were collected during the prophylaxis phase on Day +1 and Day +7 post-HSCT in a subgroup of participants in the DP arm who separately consented for this sampling. Sparse PK samples were collected from participants throughout the study according to the protocol.

NRM is defined as death that occurs after HSCT in participants who were noted as having malignant primary disease on the disease history electronic case report form (eCRF) and do not have primary disease relapse post-HSCT.

Time frame: Days +100 and +180 Post-HSCT

Population: Non-relapse mortality was assessed using the number of participants with malignant primary disease within treatment arm from the Intent-to-Treat Analysis Set.

Graft failure is defined as participants that after hematopoietic stem cell transplant (HSCT) never reached an absolute neutrophil count \>0.5 x 10\^9/L that is maintained for three consecutive days or a platelet count \>20 x 10\^9/L without a platelet transfusion in the preceding seven days. If veno-occlusive disease (VOD) occurs, the prophylaxis phase starts on the baseline date and ends on the day before the start date of rescue defibrotide. If VOD does not occur, the prophylaxis phase starts on the baseline date and ends on the date of study completion/early termination. For the subset of participants who developed VOD and received rescue defibrotide, the rescue treatment phase begins on the start date of rescue defibrotide and ends on the date of study completion/early termination.

Time frame: Day +180 Post-HSCT

Population: Number of Participants with graft failure was assessed using the Safety Analysis Set.

The date of neutrophil engraftment was recorded on the electronic case report form (eCRF) and is defined as the first date after HSCT of an absolute neutrophil count \>0.5 x 10\^9/L that is maintained for three consecutive days. The definition of absolute neutrophil count includes both segmented neutrophils and bands, immature neutrophils. The number of participants with neutrophil engraftment was assessed.

Time frame: Day +180 Post-HSCT

Population: Number of participants with neutrophil engraftment was assessed using the Safety Analysis Set.

The date of platelet engraftment was recorded on the electronic case report form (eCRF) and is defined as the first date after HSCT of a platelet count \>20 x 10\^9/L without a platelet transfusion in the preceding seven days. The number of participants with platelet engraftment was assessed.

Time frame: Day +180 Post-HSCT

Population: Number of Participants with platelet engraftment was assessed using the Safety Analysis Set.

The proportion of participants who had resolution of VOD by Day +180 post-HSCT is reported as a percentage.

Time frame: Day +180 Post-HSCT

Population: Resolution of VOD was assessed using the Intent-To-Treat Analysis Set. The overall number analyzed is the number of participants diagnosed with VOD by Day +30 post-HSCT by the investigator.

The values shown are the number and percentages of participants who developed chronic GvHD by Day +180 post-HSCT in the prophylaxis phase and rescue phase.

Time frame: Day +180 Post-HSCT

Population: Percentage of participants chronic GvHD was assessed using the Safety Analysis Set. Percentages were calculated with the number of participants in Safety Analysis Set who entered the study phase in each arm as a denominator. The number analyzed differs from the overall number of participants analyzed due to the count of participants included in the prophylaxis phase versus the rescue phase.

The number and percentage of participants with Grade 2-4 acute GvHD in the prophylaxis phase. Grade 2 is defined as Skin stage = 3, or Liver stage = 1, or GI stage = 1. Grade 3 is defined as Skin stage = 3, or Liver stage = 2-3, or GI stage = 2-4. Grade 4 is defined as a Skin stage = 4, or Liver stage = 4, or GI stage = 2-4.

Time frame: Days +30, +100, and +180 Post-HSCT

Population: Percentage of participants with acute GvHD was assessed using the Safety Analysis Set. Percentages were calculated with the number of participants in Safety Analysis Set who entered the study phase in each arm as a denominator during the prophylaxis phase.

The number and percentage of participants with Grade 2-4 acute GvHD in the rescue phase. Grade 2 is defined as Skin stage = 3, or Liver stage = 1, or GI stage = 1. Grade 3 is defined as Skin stage = 3, or Liver stage = 2-3, or GI stage = 2-4. Grade 4 is defined as a Skin stage = 4, or Liver stage = 4, or GI stage = 2-4.

Time frame: Days +30, +100, and +180 Post-HSCT

Population: Percentage of participants with acute GvHD was assessed using the Safety Analysis Set. Percentages were calculated with the number of participants in Safety Analysis Set who entered the study phase in each arm as a denominator during the rescue phase.

The values shown are the number and percentage of participants with VOD after day +30 post-HSCT and on or before Days +100 and +180 post-HSCT. The diagnosis of VOD through Day +100 post-HSCT was made by Endpoint Adjudication Committee (EPAC), and the diagnosis of VOD after Day +100 post-HSCT was based on investigator assessments.

Time frame: Days +100 and +180 Post-HSCT

Population: Percentage of VOD was assessed using the Intent-to-Treat Analysis Set.

VOD-associated MOD is defined for participants as occurring if the investigator answers Yes to the question Has the participant been diagnosed with VOD associated MOD? in the electronic case report form (eCRF). The values below are the number of participants who received the answer, Yes.

Time frame: Days +30 and +100 Post-HSCT

Population: Percentage of Participants with VOD-associated MOD was assessed using the Intent-to-Treat Analysis Set.

The number of participants who were diagnosed with VOD based on the Modified Seattle Criteria as per blinded EPAC assessment. The percentage was calculated out of the total number of participants in each arm of the study. The values reported below are the numbers and percentages of participants who experienced VOD by Day +30 post-HSCT.

Time frame: Day +30 Post-HSCT

Population: Percentage of Participants with VOD by Day +30 post-HSCT was assessed using the Intent-to-Treat Analysis Set.

Time to Resolution of VOD is calculated as follows: Time to Resolution of VOD= \[Date of VOD resolution\] - \[Date of VOD diagnosis by investigator\].

Time frame: Day +180 Post-HSCT

Population: Resolution of VOD was assessed using the Intent-To-Treat Analysis.

VOD-free survival is a composite of survival status and VOD occurrence as determined by modified Seattle criteria adjudicated by a blinded independent EPAC. An event is defined as a VOD diagnosis (as assessed by the EPAC) or death, whichever, is earlier, up to and including Day +100 post-HSCT. The values reported below are participants who did not experience VOD or death by Day +100 post-HSCT.

Time frame: Day +100 Post-HSCT

Population: VOD-free survival was assessed using the Intent-to-Treat Analysis Set.

VOD-free survival is a composite of survival status and VOD occurrence as determined by modified Seattle criteria. An event is defined as a VOD diagnosis or death, whichever, is earlier, up to and including Day +180 post-HSCT. The diagnosis of VOD through Day +100 post-HSCT was based on Endpoint Adjudication Committee (EPAC), and the diagnosis of VOD after Day +100 post-HSCT was based on investigator assessments. The values reported below are participants who did not experience VOD or death by Day +180 post-HSCT.

Time frame: Day +180 Post-HSCT

Population: VOD-free Survival by Day +180 post-HSCT was assessed using the Intent-to-Treat Analysis Set.

Mean volume of distribution following intravenous dosing. Mean volume of distribution is a summary statistic and it is not reported on an hourly basis.If veno-occlusive disease (VOD) occurs, the prophylaxis phase starts on the baseline date and ends on the day before the start date of rescue defibrotide. If VOD does not occur, the prophylaxis phase starts on the baseline date and ends on the date of study completion/early termination.

Time frame: Day +1 and +7 Post-HSCT

Population: Volume of distribution was assessed using the Pharmacokinetic (PK) Evaluable Analysis Set. Intensive PK samples were collected during the prophylaxis phase on Day +1 and Day +7 post-HSCT in a subgroup of participants in the DP arm who separately consented for this sampling. Sparse PK samples were collected from participants throughout the study according to the protocol.

Mean volume of distribution following intravenous dosing. Mean volume of distribution is a summary statistic and it is not reported on an hourly basis. For the subset of participants who developed veno-occlusive disease (VOD) and received rescue defibrotide, the rescue treatment phase begins on the start date of rescue defibrotide and ends on the date of study completion/early termination.

Time frame: Day +14 Post-VOD Treatment

Population: Volume of distribution was assessed using the Pharmacokinetic (PK) Evaluable Analysis Set. Frequent PK samples were collected from participants who developed VOD and received defibrotide rescue treatment (rescue phase) on VOD treatment Day 14. Sparse PK samples were collected from participants throughout the study according to the protocol.