An Open-Label Study of Defibrotide for the Prevention of Acute Graft-versus-Host-Disease (AGvHD)

NCT03339297 — Phase 2, Completed, 152 participants, Jazz Pharmaceuticals

ClinicalTrials Daily · Areas · Conditions · Drugs · Sponsors ·

A Phase 2, Prospective, Randomized, Open-Label Study on the Efficacy of Defibrotide Added to Standard of Care Immunoprophylaxis for the Prevention of Acute Graft-versus-Host-Disease in Adult and Pediatric Patients After Allogeneic Hematopoietic Stem Cell Transplant

Registry	NCT03339297
Status	Completed
Phase	Phase 2
Study type	Interventional; randomized, parallel, masking: none, treatment
Enrollment	152 (Actual)
Sponsor	Jazz Pharmaceuticals (Industry)
Conditions	Graft-versus-host Disease, Acute-graft-versus-host Disease
Interventions	Defibrotide, Standard of Care (Drug)
Dates	start 2018-02-21, primary completion 2020-05-12, completion 2020-05-12, first posted 2017-11-13, last updated 2021-08-18
Locations	62 sites in United States, Austria, Belgium, Bulgaria, Canada, Croatia, France, Germany and 6 more countries

-Summary

This is a study comparing the defibrotide prophylaxis arm vs standard of care arm for the prevention of aGvHD.

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+Arms and interventions

Arm	Type	Interventions	Description
Defibrotide Prophylaxis	Experimental	Drug: Defibrotide; Drug: Standard of Care	Standard of Care Immunoprophylaxis + Defibrotide
Standard of Care	Active comparator	Drug: Standard of Care	Standard of Care Immunoprophylaxis Alone

Defibrotide (Drug): 6.25 mg/kg via 2-hour IV infusion every 6 hours
Standard of Care (Drug): Administered according to local institutional guidelines, physician preference, and patient need.

+Outcome measures

Primary outcomes

Cumulative Incidence Percentage of Grade B to D Acute Graft Versus Host Disease (aGvHD) by Day +100 Post-Hematopoietic Stem Cell Transplant (HSCT) [HSCT Day (Day +0 post-HSCT) through Day +100 post-HSCT]: Cumulative Incidence Percentage of Grade B to D aGvHD was defined using the International Bone Marrow Transplant Registry (IBMTR) Severity Index. Grade B is defined as Skin stage = 2 or Liver stage = 1 to 2 or GI stage = 1 to 2. Grade C is defined as Skin stage = 3 or Liver stage = 3 or GI stage = 3. Grade D is defined as a Skin stage = 4 or Liver stage = 4 or GI stage = 4.

Secondary outcomes

Cumulative Incidence Percentage of Grade B to D aGvHD by Day +180 Post-HSCT [HSCT Day (Day +0 post-HSCT) through Day +180 post-HSCT]: Cumulative Incidence Percentage of Grade B to D aGvHD was defined using the IBMTR Severity Index. Grade B is defined as Skin stage = 2 or Liver stage = 1 to 2 or GI stage = 1 to 2. Grade C is defined as Skin stage = 3 or Liver stage = 3 or GI stage = 3. Grade D is defined as a Skin stage = 4 or Liver stage = 4 or GI stage = 4.
Kaplan-Meier Estimate of Grade B to D aGvHD-free Survival by Days +100 and +180 Post-HSCT [HSCT Day (Day +0 post-HSCT) through Days +100 and +180 post-HSCT]: Grade B to D aGvHD was defined using the IBMTR Severity Index. Grade B is defined as Skin stage = 2 or Liver stage = 1 to 2 or GI stage = 1 to 2. Grade C is defined as Skin stage = 3 or Liver stage = 3 or GI stage = 3. Grade D is defined as a Skin stage = 4 or Liver stage = 4 or GI stage = 4.
Cumulative Incidence Percentage of Grade C to D aGvHD by Days +100 and +180 Post-HSCT [HSCT Day (Day +0 post-HSCT) through Days +100 and +180 post-HSCT]: Cumulative Incidence Percentage of Grade C to D aGvHD was defined using the IBMTR Severity Index. Grade C is defined as Skin stage = 3 or Liver stage = 3 or GI stage = 3. Grade D is defined as a Skin stage = 4 or Liver stage = 4 or GI stage = 4.
Cumulative Incidence Percentage of Disease Relapse by Days +100 and +180 Post-HSCT [HSCT Day (Day +0 post-HSCT) through Days +100 and +180 post-HSCT]: Disease relapse was defined by either morphological evidence of acute leukemia or Myelodysplastic syndrome (MDS) consistent with pre-transplant features, documented or not by biopsy. The event was defined as an increase in size of prior sites of disease or evidence of new sites of disease, documented or not by biopsy. Disease relapse was diagnosed when there was morphological or clinical evidence of the following: reappearance of leukemia blast cells in the peripheral blood, or >5% blasts in the bone marrow (BM), not attributable to another cause (eg, BM regeneration), or the appearance of previous or new dysplastic changes (MDS specific) within the BM, with or without falling donor chimerism, or the development of extramedullary leukemia or leukemic cells in the cerebral spinal fluid, or institution of therapy to treat relapsed disease, including donor lymphocyte infusion.
Cumulative Incidence Percentage of Systemic Steroids for the Treatment of aGvHD +180 Days Post-HSCT [HSCT Day (Day +0 post-HSCT) through Day +180 post-HSCT]: For each treatment arm, the cumulative incidence rate of systemic steroid use for the treatment of aGvHD by Day +180 post-HSCT will be estimated using the cumulative incidence competing risk estimator. The calculation of the cumulative incidence rates and the stratified Gray's test was carried out using the LIFETEST procedure in SAS version 9.4. If the participant experienced a competing risk event, then the initiation date was used to calculate the time-to-event variable.
Change From Baseline to Days +100 and +180 Post-HSCT in the Physical Wellbeing Subscale as Measured by the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Questionnaire Score [Baseline through Days +100 and +180 post-HSCT]: The Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) total score is the sum of the FACT physical wellbeing score, the FACT social/family wellbeing score, the FACT emotional wellbeing score, the FACT functional wellbeing score, and the FACT-BMT subscale. The FACT physical wellbeing subscale scores range from a minimum of 0 to a maximum of 28, with higher scores indicating better quality of life. A negative change from baseline indicates a decrease in score.
Change From Baseline to Days +100 and +180 Post-HSCT in the Social/Family Wellbeing Subscale as Measured by the FACT-BMT Questionnaire Score [Baseline through Days +100 and +180 post-HSCT]: The Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) total score is the sum of the FACT physical wellbeing score, the FACT social/family wellbeing score, the FACT emotional wellbeing score, the FACT functional wellbeing score, and the FACT-BMT subscale. The FACT social/family wellbeing subscale scores range from a minimum of 0 to a maximum of 28, with higher scores indicating better quality of life. A negative change from baseline indicates a decrease in score.
Change From Baseline to Days +100 and +180 Post-HSCT in the Emotional Wellbeing Subscale as Measured by the FACT-BMT Questionnaire Score [Baseline through Days +100 and +180 post-HSCT]: The Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) total score is the sum of the FACT physical wellbeing score, the FACT social/family wellbeing score, the FACT emotional wellbeing score, the FACT functional wellbeing score, and the FACT-BMT subscale. The FACT emotional wellbeing subscale scores range from a minimum of 0 to a maximum of 24, with higher scores indicating better quality of life.
Change From Baseline to Days +100 and +180 Post-HSCT in the Functional Wellbeing Subscale as Measured by the FACT-BMT Questionnaire Score [Baseline through Days +100 and +180 post HSCT]: The Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) total score is the sum of the FACT physical wellbeing score, the FACT social/family wellbeing score, the FACT emotional wellbeing score, the FACT functional wellbeing score, and the FACT-BMT subscale. The FACT functional wellbeing subscale scores range from a minimum of 0 to a maximum of 28, with higher scores indicating better quality of life. A negative change from baseline indicates a decrease in score.
Change From Baseline to Days +100 and +180 Post-HSCT in the Bone Marrow Transplantation Subscale (BMTS) as Measured by the FACT-BMT Questionnaire Score [Baseline through Days +100 and +180 post-HSCT]: The Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) total score is the sum of the FACT physical wellbeing score, the FACT social/family wellbeing score, the FACT emotional wellbeing score, the FACT functional wellbeing score, and the FACT-BMT subscale. The FACT-BMT subscale scores range from a minimum of 0 to a maximum of 40, with higher scores indicating better quality of life. A negative change from baseline indicates a decrease in score.
Change From Baseline to Days +100 and +180 Post-HSCT in the General (FACT-G) Questionnaire Score [Baseline through Days +100 and +180 post-HSCT]: The FACT-General (FACT-G) is a core component of the FACT-BMT, and includes 4 of the 5 subscales included in the FACT-BMT total score (FACT physical wellbeing score, FACT social/family wellbeing score, FACT emotional wellbeing score, the FACT functional wellbeing score). In line with this similarity, results of the FACT-G exhibited the same pattern as described for the FACT-BMT total score. The FACT-G scores range from a minimParticipants were age ≥16 years at baseline.
Change From Baseline to Days +100 and +180 Post-HSCT in the FACT-BMT Total Score [Baseline through Days +100 and +180 post-HSCT]: The Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) total score is the sum of the FACT physical wellbeing score, the FACT social/family wellbeing score, the FACT emotional wellbeing score, the FACT functional wellbeing score, and the FACT-BMT subscale. The FACT-BMT total score range is from a minimum of 0 to a maximum of 148, with higher scores indicating better quality of life. A negative change from baseline indicates a decrease in score.
Change From Baseline to Days +100 and +180 Post-HSCT in the Functional Assessment of Cancer Therapy-Bone Marrow Transplant-Trial Outcomes Index (FACT-BMT-TOI) [Baseline through Days +100 and +180 post-HSCT]: The FACT-BMT-TOI is defined as the sum of the FACT physical wellbeing score, the FACT functional wellbeing score, and the FACT-BMT subscale. Scores range from a minimum of 0 to a maximum of 96, with higher scores indicating better quality of life. A negative change from baseline indicates a decrease in score.
Change From Baseline to Days +100 and +180 Post-HSCT in Participant Reported Outcomes Measured Based on the EQ-5D-5L Index Value for Health States [Baseline through Days +100 and +180 post-HSCT]: The 5-Level EuroQol-5D health questionnaire (EQ-5D-5L) index value, which is country-specific, was only performed for participants in the US. The EQ-5D-5L is a standardized instrument for use as a measure of health outcome that includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Change from the baseline assessment to Days +100 and +180 post-HSCT in the index value was assessed. The index value total range is from a minimum value of -1 to a maximum value of +1. A higher EQ-5D-5L index value represents better quality of life (QoL), thus a positive change in the index value represents improved QoL.
Change From Baseline to Days +100 and +180 Post-HSCT in Participant Reported Outcomes as Measured Based on the EQ Visual Analog Scale (EQ VAS) [Baseline through Days +100 and +180 post-HSCT]: The EQ VAS score at baseline and each of the post-HSCT assessments was summarized and presented using descriptive statistics. A higher EQ VAS score represents better QoL. For each of the post-HSCT assessments, change between baseline and that assessment in the EQ VAS score was calculated similarly to the EQ-5D-5L index value for a specific participant and was summarized and presented using descriptive statistics. The score ranges from a minimum of 0 and a maximum of 100. A negative change in the score indicates a decrease in quality of life.
Change From Baseline to Day +100 Post-HSCT in 5-Level European Quality of Life (EQ-5D-5L) Mobility Dimension for Participants With Age >=16 Years [Baseline through Day +100 post-HSCT]: The EQ-5D-5L is a standardized instrument for use as a measure of health outcome that includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of the 5 dimensions based on the descriptive system of the EQ-5D-5L, the numbers of participants for all categories (the 5 levels of reported problems) were assessed. For Day +100 Post-HSCT change between baseline in each dimension will be categorized as follows for a specific participant: Condition improved, if the reported level of problem is lower at that assessment than at 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; Unknown, if the reported level of problem is not completed or missing either at baseline or at that assessment.
Change From Baseline to Day +180 Post-HSCT in 5-Level European Quality of Life (EQ-5D-5L) Mobility Dimension for Participants With Age >=16 Years [Baseline through Day +180 post-HSCT]: The EQ-5D-5L is a standardized instrument for use as a measure of health outcome that includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of the 5 dimensions based on the descriptive system of the EQ-5D-5L, the numbers of participants for all categories (the 5 levels of reported problems) were assessed. For Day +180 Post-HSCT change between baseline in each dimension will be categorized as follows for a specific participant: Condition improved, if the reported level of problem is lower at that assessment than at 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; Unknown, if the reported level of problem is not completed or missing either at baseline or at that assessment.
Change From Baseline to Day +100 Post-HSCT in 5-Level European Quality of Life (EQ-5D-5L) Pain/Discomfort Dimension for Participants With Age >=16 Years [Baseline through Day +100 post-HSCT]: The EQ-5D-5L is a standardized instrument for use as a measure of health outcome that includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of the 5 dimensions based on the descriptive system of the EQ-5D-5L, the numbers of participants for all categories (the 5 levels of reported problems) were assessed. For Days +100 Post-HSCT change between baseline in each dimension will be categorized as follows for a specific participant: Condition improved, if the reported level of problem is lower at that assessment than at 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; Unknown, if the reported level of problem is not completed or missing either at baseline or at that assessment.
Change From Baseline to Day +180 Post-HSCT in 5-Level European Quality of Life (EQ-5D-5L) Pain/Discomfort Dimension for Participants With Age >=16 Years [Baseline through Day +180 post-HSCT]: The EQ-5D-5L is a standardized instrument for use as a measure of health outcome that includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of the 5 dimensions based on the descriptive system of the EQ-5D-5L, the numbers of participants for all categories (the 5 levels of reported problems) were assessed. For Day +180 Post-HSCT change between baseline in each dimension will be categorized as follows for a specific participant: Condition improved, if the reported level of problem is lower at that assessment than at 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; Unknown, if the reported level of problem is not completed or missing either at baseline or at that assessment.
Change From Baseline to Day +100 Post-HSCT in 5-Level European Quality of Life (EQ-5D-5L) Self-Care Dimension for Participants With Age >=16 Years [Baseline through Day +100 post-HSCT]: The EQ-5D-5L is a standardized instrument for use as a measure of health outcome that includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of the 5 dimensions based on the descriptive system of the EQ-5D-5L, the numbers of participants for all categories (the 5 levels of reported problems) were assessed. For Day +100 Post-HSCT change between baseline in each dimension will be categorized as follows for a specific participant: Condition improved, if the reported level of problem is lower at that assessment than at 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; Unknown, if the reported level of problem is not completed or missing either at baseline or at that assessment.
Change From Baseline to Day +180 Post-HSCT in 5-Level European Quality of Life (EQ-5D-5L) Self-Care Dimension for Participants With Age >=16 Years [Baseline through Day +180 post-HSCT]: The EQ-5D-5L is a standardized instrument for use as a measure of health outcome that includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of the 5 dimensions based on the descriptive system of the EQ-5D-5L, the numbers of participants for all categories (the 5 levels of reported problems) were assessed. For Day +180 Post-HSCT change between baseline in each dimension will be categorized as follows for a specific participant: Condition improved, if the reported level of problem is lower at that assessment than at 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; Unknown, if the reported level of problem is not completed or missing either at baseline or at that assessment.
Change From Baseline to Day +100 Post-HSCT in 5-Level European Quality of Life (EQ-5D-5L) Usual Activities Dimension for Participants With Age >=16 Years [Baseline through Day +100 post-HSCT]: The EQ-5D-5L is a standardized instrument for use as a measure of health outcome that includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of the 5 dimensions based on the descriptive system of the EQ-5D-5L, the numbers of participants for all categories (the 5 levels of reported problems) were assessed. For Day +100 Post-HSCT change between baseline in each dimension will be categorized as follows for a specific participant: Condition improved, if the reported level of problem is lower at that assessment than at 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; Unknown, if the reported level of problem is not completed or missing either at baseline or at that assessment.
Change From Baseline to Day +180 Post-HSCT in 5-Level European Quality of Life (EQ-5D-5L) Usual Activities Dimension for Participants With Age >=16 Years [Baseline through Day +180 post-HSCT]: The EQ-5D-5L is a standardized instrument for use as a measure of health outcome that includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of the 5 dimensions based on the descriptive system of the EQ-5D-5L, the numbers of participants for all categories (the 5 levels of reported problems) were assessed. For Day +180 Post-HSCT change between baseline in each dimension will be categorized as follows for a specific participant: Condition improved, if the reported level of problem is lower at that assessment than at 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; Unknown, if the reported level of problem is not completed or missing either at baseline or at that assessment.
Change From Baseline to Day +100 Post-HSCT in 5-Level European Quality of Life (EQ-5D-5L) Anxiety/Depression Dimension for Participants With Age >=16 Years [Baseline through Day +100 post-HSCT]: The EQ-5D-5L is a standardized instrument for use as a measure of health outcome that includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of the 5 dimensions based on the descriptive system of the EQ-5D-5L, the numbers of participants for all categories (the 5 levels of reported problems) were assessed. For Day +100 Post-HSCT change between baseline in each dimension will be categorized as follows for a specific participant: Condition improved, if the reported level of problem is lower at that assessment than at 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; Unknown, if the reported level of problem is not completed or missing either at baseline or at that assessment.
Change From Baseline to Day +180 Post-HSCT in 5-Level European Quality of Life (EQ-5D-5L) Anxiety/Depression Dimension for Participants With Age >=16 Years [Baseline through Day +180 post-HSCT]: The EQ-5D-5L is a standardized instrument for use as a measure of health outcome that includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of the 5 dimensions based on the descriptive system of the EQ-5D-5L, the numbers of participants for all categories (the 5 levels of reported problems) were assessed. For Day +180 Post-HSCT change between baseline in each dimension will be categorized as follows for a specific participant: Condition improved, if the reported level of problem is lower at that assessment than at 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; Unknown, if the reported level of problem is not completed or missing either at baseline or at that assessment.

+Eligibility

Sex: All, ages: 1 Year to any

Inclusion Criteria:

1. Participant must be ≥1 year of age at screening and undergoing allogeneic Hematopoietic Stem Cell Transplant (HSCT).
2. Participant must be diagnosed with acute leukemia in morphologic complete remission (CR1 or CR2) or with Myelodysplastic syndrome (MDS) with no circulating blasts and with less than 5% blasts in the bone marrow
3. Participant must have planned to receive either a myeloablative or reduced-intensity conditioning regimen and have an unrelated donor who is human leukocyte antigen (HLA) matched or single-allele mismatched
4. Participant must receive the following medical regimen as part of standard of care immunoprophylaxis for GvHD in either study arm at doses and regimen determined by local institutional guidelines, physician preference, and participant need:

Methotrexate (MTX) or Mycophenolate mofetil (MMF) + calcineurin inhibitor (Cyclosporine A \[CSA\] or Tacrolimus \[TAC\]) +/- Anti-thymocyte globulin (ATG) (ATG use is limited to 30% of participants).
5. Graft must be a CD3+ T-cell replete peripheral blood stem cell (PBSC) graft or non-manipulated bone marrow (BM) graft.
6. Adult participants must be able to understand and sign a written informed consent. For pediatric participants, the parent/legal guardian or representative must be able to understand and sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.

Exclusion Criteria:

1. Participant has had a prior autologous or allogeneic HSCT.
2. Participant is using or plans to use an investigational agent for the prevention of GvHD.
3. Participant is receiving or plans to receive other investigational therapy and/or is enrolled or plans to enroll in a separate clinical study.
4. Participant, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
5. Participant has a psychiatric illness that would prevent the participant or legal guardian or representative from giving informed consent and/or assent.
6. Participant has a serious active disease or co-morbid medical condition, as judged by the investigator, which would interfere with the conduct of this study.
7. Participant is pregnant or lactating and does not agree to stop breastfeeding.
8. Any other condition that would cause a risk to the participant if he/she participated in the trial.
9. Participant has a known history of hypersensitivity to defibrotide or any of the excipients.
10. Participant had acute bleeding that is clinically significant within 24 hours before the start of study treatment, defined as either of the following:

* Hemorrhage requiring >15 cc/kg of packed red blood cells (eg, pediatric participant weighing 20 kg and requiring 300 cc packed red blood cells/24 hours, or an adult weighing >70 kg and requiring 3 units of packed red blood cells/24hours) to replace blood loss, or
* Bleeding from a site which, in the investigator's opinion, constituted a potential life-threatening source (eg, pulmonary hemorrhage or central nervous system bleeding), irrespective of amount of blood loss
11. Participant used any medication that increases the risk of bleeding within 24 hours before the start of study treatment, including, but not limited to, systemic heparin, low molecular weight heparin, heparin analogs, alteplase, streptokinase, urokinase, antithrombin III, oral anticoagulants including warfarin, and other agents that increase the risk of bleeding. Participants may have received heparin or other anticoagulants for routine central venous line management and intermittent dialysis or ultrafiltration. Fibrinolytic instillation for central venous line occlusion was also permitted. Note: Heparin used to keep catheters open was allowed (up to 100 U/kg/day).

+Posted results

Participant flow

Milestone	Defibrotide Prophylaxis	Standard of Care Immunoprophylaxis
Started	79	73
Completed	56	59
Not completed	23	14

Outcome results

Cumulative Incidence Percentage of Grade B to D Acute Graft Versus Host Disease (aGvHD) by Day +100 Post-Hematopoietic Stem Cell Transplant (HSCT) (Primary), Number, cumulative incidence percentage: Defibrotide Prophylaxis 38.4; Standard of Care Immunoprophylaxis 47.1
Cumulative Incidence Percentage of Grade B to D aGvHD by Day +180 Post-HSCT (Secondary), Number, cumulative incidence percentage: Defibrotide Prophylaxis 50.6; Standard of Care Immunoprophylaxis 51.6
Kaplan-Meier Estimate of Grade B to D aGvHD-free Survival by Days +100 and +180 Post-HSCT (Secondary), Number, percentage of participants: Defibrotide Prophylaxis 60.3; Standard of Care Immunoprophylaxis 51.4
Cumulative Incidence Percentage of Grade C to D aGvHD by Days +100 and +180 Post-HSCT (Secondary), Number, cumulative incidence percentage: Defibrotide Prophylaxis 16.5; Standard of Care Immunoprophylaxis 21.5
Cumulative Incidence Percentage of Disease Relapse by Days +100 and +180 Post-HSCT (Secondary), Number, cumulative incidence percentage: Defibrotide Prophylaxis 11.0; Standard of Care Immunoprophylaxis 4.3
Cumulative Incidence Percentage of Systemic Steroids for the Treatment of aGvHD +180 Days Post-HSCT (Secondary), Number, cumulative incidence percentage: Defibrotide Prophylaxis 38.2; Standard of Care Immunoprophylaxis 28.6
Change From Baseline to Days +100 and +180 Post-HSCT in the Physical Wellbeing Subscale as Measured by the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Questionnaire Score (Secondary), Mean, unit on a scale: Defibrotide Prophylaxis -1.25 +/- 5.069; Standard of Care Immunoprohylaxis -1.41 +/- 6.371
Change From Baseline to Days +100 and +180 Post-HSCT in the Social/Family Wellbeing Subscale as Measured by the FACT-BMT Questionnaire Score (Secondary), Mean, unit on a scale: Defibrotide Prophylaxis -0.56 +/- 3.488; Standard of Care Immunoprophylaxis -0.29 +/- 5.716
Change From Baseline to Days +100 and +180 Post-HSCT in the Emotional Wellbeing Subscale as Measured by the FACT-BMT Questionnaire Score (Secondary), Mean, unit on a scale: Defibrotide Prophylaxis 1.47 +/- 4.910; Standard of Care Immunoprophylaxis 1.47 +/- 3.659
Change From Baseline to Days +100 and +180 Post-HSCT in the Functional Wellbeing Subscale as Measured by the FACT-BMT Questionnaire Score (Secondary), Mean, unit on a scale: Defibrotide Prophylaxis -1.71 +/- 5.622; Standard of Care Immunoprophylaxis -2.11 +/- 5.962
Change From Baseline to Days +100 and +180 Post-HSCT in the Bone Marrow Transplantation Subscale (BMTS) as Measured by the FACT-BMT Questionnaire Score (Secondary), Mean, unit on a scale: Defibrotide Prophylaxis -0.88 +/- 5.484; Standard of Care Immunoprophylaxis -2.14 +/- 5.900
Change From Baseline to Days +100 and +180 Post-HSCT in the General (FACT-G) Questionnaire Score (Secondary), Mean, unit on a scale: Defibrotide Prophylaxis -2.38 +/- 12.623; Standard of Care Immunoprophylaxis -1.74 +/- 15.623
Change From Baseline to Days +100 and +180 Post-HSCT in the FACT-BMT Total Score (Secondary), Mean, unit on a scale: Defibrotide Prophylaxis -3.24 +/- 16.036; Standard of Care Immunoprophylaxis -3.70 +/- 19.854
Change From Baseline to Days +100 and +180 Post-HSCT in the Functional Assessment of Cancer Therapy-Bone Marrow Transplant-Trial Outcomes Index (FACT-BMT-TOI) (Secondary), Mean, unit on a scale: Defibrotide Prophylaxis -3.88 +/- 13.110; Standard of Care Immunoprophylaxis -5.24 +/- 15.575
Change From Baseline to Days +100 and +180 Post-HSCT in Participant Reported Outcomes Measured Based on the EQ-5D-5L Index Value for Health States (Secondary), Mean, unit on a scale: Defibrotide Prophylaxis 0.02 +/- 0.092; Standard of Care Immunoprophylaxis -0.01 +/- 0.101
Change From Baseline to Days +100 and +180 Post-HSCT in Participant Reported Outcomes as Measured Based on the EQ Visual Analog Scale (EQ VAS) (Secondary), Mean, unit on a scale: Defibrotide Prophylaxis 6.03 +/- 20.599; Standard of Care Immunoprophylaxis 2.70 +/- 15.004
Change From Baseline to Day +100 Post-HSCT in 5-Level European Quality of Life (EQ-5D-5L) Mobility Dimension for Participants With Age >=16 Years (Secondary), Count of participants, Participants: Defibrotide Prophylaxis 3; Standard of Care Immunoprophylaxis 4
Change From Baseline to Day +180 Post-HSCT in 5-Level European Quality of Life (EQ-5D-5L) Mobility Dimension for Participants With Age >=16 Years (Secondary), Count of participants, Participants: Defibrotide Prophylaxis 3; Standard of Care Immunoprophylaxis 3
Change From Baseline to Day +100 Post-HSCT in 5-Level European Quality of Life (EQ-5D-5L) Pain/Discomfort Dimension for Participants With Age >=16 Years (Secondary), Count of participants, Participants: Defibrotide Prophylaxis 10; Standard of Care Immunoprophylaxis 9
Change From Baseline to Day +180 Post-HSCT in 5-Level European Quality of Life (EQ-5D-5L) Pain/Discomfort Dimension for Participants With Age >=16 Years (Secondary), Count of participants, Participants: Defibrotide Prophylaxis 6; Standard of Care Immunoprophylaxis 8
6 more outcome measures not shown.

Adverse events

Time frame: All Adverse Events (AEs) and Serious Adverse Events (SAEs) were reported from the time of signed informed consent form (ICF) and were recorded up to Day +63 post-HSCT. SAEs considered by the investigator to be related to study drug or study procedures were reported up to Day +180 post-HSCT.

Arm	Deaths	Serious adverse events	Other adverse events
Defibrotide Prophylaxis	10/74 (13.5%)	31/74 (41.9%)	74/74 (100.0%)
Standard of Care Immunoprophylaxis	9/70 (12.9%)	31/70 (44.3%)	70/70 (100.0%)

Serious adverse events by term

Term	Organ system	Defibrotide Prophylaxis	Standard of Care Immunoprophylaxis
Obstructive shock	Vascular disorders	0/74	1/70
Shock	Vascular disorders	0/74	1/70
Venoocclusive disease	Vascular disorders	1/74	1/70
Acute lymphocytic leukaemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	0/74	1/70
Acute myeloid leukaemia recurrent	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	0/74	1/70
Epstein-Barr virus associated lymphoproliferative disorder	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	0/74	1/70
Acute graft versus host disease	Immune system disorders	4/74	1/70
Acute graft versus host disease in skin	Immune system disorders	1/74	4/70
Graft versus host disease	Immune system disorders	0/74	1/70
Graft versus host disease in liver	Immune system disorders	0/74	1/70
Acute graft versus host disease in intestine	Immune system disorders	2/74	1/70
General physical health deterioration	General disorders	0/74	1/70
Mucosal haemorrhage	General disorders	1/74	0/70
Mucosal inflammation	General disorders	1/74	0/70
Multiple organ dysfunction syndrome	General disorders	1/74	1/70
Pyrexia	General disorders	1/74	0/70
Toxicity to various agents	Injury, poisoning and procedural complications	0/74	1/70
Transfusion reaction	General disorders	0/74	1/70
Blood potassium decreased	Investigations	0/74	1/70
Ejection fraction decreased	Investigations	0/74	1/70
Atrial flutter	Cardiac disorders	1/74	0/70
Cardiac tamponade	Cardiac disorders	0/74	1/70
Cardio-respiratory arrest	Cardiac disorders	1/74	0/70
Cardiogenic shock	Cardiac disorders	1/74	1/70
Sinus tachycardia	Cardiac disorders	1/74	0/70
Stress cardiomyopathy	Cardiac disorders	0/74	1/70
Supraventricular tachycardia	Cardiac disorders	1/74	0/70
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	1/74	1/70
Dyspnoea	Respiratory, thoracic and mediastinal disorders	3/74	0/70
Epistaxis	Respiratory, thoracic and mediastinal disorders	1/74	0/70
Lung disorder	Respiratory, thoracic and mediastinal disorders	0/74	1/70
Pharyngeal inflammation	Respiratory, thoracic and mediastinal disorders	0/74	1/70
Pleural effusion	Respiratory, thoracic and mediastinal disorders	0/74	1/70
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	0/74	1/70
Pulmonary oedema	Respiratory, thoracic and mediastinal disorders	0/74	1/70
Respiratory failure	Respiratory, thoracic and mediastinal disorders	1/74	1/70
Eosinophilia	Blood and lymphatic system disorders	1/74	0/70
Evans syndrome	Blood and lymphatic system disorders	1/74	0/70
Febrile neutropenia	Blood and lymphatic system disorders	1/74	0/70
Thrombotic microangiopathy	Blood and lymphatic system disorders	1/74	0/70
Cognitive disorder	Nervous system disorders	1/74	0/70
Hypertensive encephalopathy	Nervous system disorders	0/74	1/70
Syncope	Nervous system disorders	1/74	0/70
Abdominal pain	Gastrointestinal disorders	1/74	0/70
Acute abdomen	Gastrointestinal disorders	0/74	1/70
Diarrhoea	Gastrointestinal disorders	3/74	2/70
Intestinal haemorrhage	Gastrointestinal disorders	0/74	1/70
Nausea	Gastrointestinal disorders	2/74	1/70
Oesophagitis	Gastrointestinal disorders	1/74	0/70
Stomatitis	Gastrointestinal disorders	0/74	1/70
Upper gastrointestinal haemorrhage	Gastrointestinal disorders	1/74	0/70
Vomiting	Gastrointestinal disorders	2/74	1/70
Venoocclusive liver disease	Hepatobiliary disorders	0/74	2/70
Acute kidney injury	Renal and urinary disorders	3/74	2/70
Cystitis haemorrhagic	Renal and urinary disorders	1/74	1/70
Rash vesicular	Skin and subcutaneous tissue disorders	1/74	0/70
Toxic skin eruption	Skin and subcutaneous tissue disorders	1/74	0/70
Decreased appetite	Metabolism and nutrition disorders	2/74	1/70
Dehydration	Metabolism and nutrition disorders	0/74	1/70
Failure to thrive	Metabolism and nutrition disorders	1/74	0/70

22 more terms not shown.

Other adverse events by term

Term	Organ system	Defibrotide Prophylaxis	Standard of Care Immunoprophylaxis
Flushing	Vascular disorders	4/74	4/70
Hypertension	Vascular disorders	25/74	29/70
Hypotension	Vascular disorders	13/74	11/70
Orthostatic hypotension	Vascular disorders	6/74	3/70
Graft versus host disease in skin	Immune system disorders	4/74	2/70
Asthenia	General disorders	9/74	6/70
Catheter site pain	General disorders	8/74	9/70
Chills	General disorders	7/74	6/70
Fatigue	General disorders	25/74	25/70
Mucosal inflammation	General disorders	10/74	17/70
Oedema peripheral	General disorders	19/74	21/70
Pain	General disorders	5/74	6/70
Pyrexia	General disorders	28/74	24/70
Agitation	Psychiatric disorders	5/74	3/70
Anxiety	Psychiatric disorders	11/74	9/70
Confusional state	Psychiatric disorders	5/74	3/70
Delirium	Psychiatric disorders	4/74	2/70
Depression	Psychiatric disorders	7/74	2/70
Insomnia	Psychiatric disorders	22/74	16/70
Fall	Injury, poisoning and procedural complications	5/74	2/70
Infusion related reaction	Injury, poisoning and procedural complications	4/74	6/70
Limb injury	Injury, poisoning and procedural complications	4/74	1/70
Skin abrasion	Injury, poisoning and procedural complications	1/74	4/70
Alanine aminotransferase increased	Investigations	3/74	7/70
Aspartate aminotransferase increased	Investigations	2/74	5/70
Bacterial test positive	Investigations	4/74	3/70
Blood bilirubin increased	Investigations	3/74	5/70
Blood creatinine increased	Investigations	12/74	6/70
Blood magnesium decreased	Investigations	1/74	4/70
C-reactive protein increased	Investigations	4/74	5/70
Epstein-Barr virus test positive	Investigations	4/74	2/70
Neutrophil count decreased	Investigations	8/74	11/70
Platelet count decreased	Investigations	19/74	21/70
Transaminases increased	Investigations	4/74	6/70
Weight decreased	Investigations	3/74	4/70
White blood cell count decreased	Investigations	8/74	6/70
Sinus tachycardia	Cardiac disorders	9/74	8/70
Cough	Respiratory, thoracic and mediastinal disorders	17/74	16/70
Dyspnoea	Respiratory, thoracic and mediastinal disorders	8/74	12/70
Epistaxis	Respiratory, thoracic and mediastinal disorders	12/74	11/70
Hiccups	Respiratory, thoracic and mediastinal disorders	5/74	3/70
Hypoxia	Respiratory, thoracic and mediastinal disorders	4/74	3/70
Nasal congestion	Respiratory, thoracic and mediastinal disorders	4/74	1/70
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	9/74	12/70
Pleural effusion	Respiratory, thoracic and mediastinal disorders	4/74	3/70
Productive cough	Respiratory, thoracic and mediastinal disorders	5/74	0/70
Rales	Respiratory, thoracic and mediastinal disorders	4/74	2/70
Rhinitis allergic	Respiratory, thoracic and mediastinal disorders	2/74	4/70
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	6/74	9/70
Tachypnoea	Respiratory, thoracic and mediastinal disorders	4/74	2/70
Anaemia	Blood and lymphatic system disorders	27/74	30/70
Febrile neutropenia	Blood and lymphatic system disorders	30/74	20/70
Leukopenia	Blood and lymphatic system disorders	9/74	6/70
Neutropenia	Blood and lymphatic system disorders	12/74	17/70
Thrombocytopenia	Blood and lymphatic system disorders	19/74	19/70
Dizziness	Nervous system disorders	10/74	8/70
Dysgeusia	Nervous system disorders	10/74	9/70
Headache	Nervous system disorders	31/74	23/70
Restless legs syndrome	Nervous system disorders	5/74	1/70
Somnolence	Nervous system disorders	5/74	2/70

62 more terms not shown.

+Locations (62)

Facility	City	Country
USC Norris Cancer Center	Los Angeles, California	United States
Mattel Children's Hospital UCLA	Los Angeles, California	United States
Stanford University	Palo Alto, California	United States
University of California, San Francisco Medical Center	San Francisco, California	United States
Mayo Clinic Jacksonville - PPDS	Jacksonville, Florida	United States
Blood & Marrow Transplant Center	Orlando, Florida	United States
Emory University Hospital	Atlanta, Georgia	United States
Northwestern Memorial Hospital	Chicago, Illinois	United States
University of Kansas Medical Center	Westwood, Kansas	United States
James Graham Brown Cancer Center	Louisville, Kentucky	United States
Ochsner Clinic Foundation	New Orleans, Louisiana	United States
University of Nebraska Medical Center	Omaha, Nebraska	United States
Montefiore Einstein Cancer Center	The Bronx, New York	United States
University of North Carolina at Chapel Hill	Chapel Hill, North Carolina	United States
Penn State Milton S Hershey Medical Center	Hershey, Pennsylvania	United States
MUSC-Hollings Cancer Center	Charleston, South Carolina	United States
VA Puget Sound Health Care System	Seattle, Washington	United States
West Virginia University Hospital	Morgantown, West Virginia	United States
Universitätsklinikum Innsbruck	Innsbruck	Austria
Ordensklinikum Linz, Krankenhaus der Elisabethinen GmbH	Linz	Austria
Cliniques Universitaires Saint-Luc	Brussels	Belgium
UZ Gent	Ghent	Belgium
UZ Leuven	Leuven	Belgium
Specialized Hospital for Active Treatment of Haematological Diseases - Sofia	Sofia	Bulgaria
Hôpital Maisonneuve-Rosemont	Montreal	Canada
Sainte Justine Hospital	Montreal	Canada
McGill University Health Center	Montreal	Canada
Klinichki Bolnicki Centar Zagreb	Zagreb	Croatia
Hospital d Instructions des Armees Percy	Clamart	France
CHRU Lille	Lille	France
Institut Universitaire du Cancer de Toulouse - Oncopole	Toulouse	France
Institut Gustave Roussy	Villejuif	France
Helios Klinikum Berlin Buch	Berlin	Germany
Medizinische Universitätsklinik Knappschaftskrankenhaus	Bochum	Germany
Klinikum Frankfurt (Oder) GmbH	Brandenburg	Germany
Uniklinik Köln	Cologne	Germany
Universitätsklinikum Carl Gustav Carus an der TU Dresden	Dresden	Germany
University Medicine Göttingen Germany	Göttingen	Germany
Universitaetsklinikum Halle (Saale)	Halle	Germany
Universitatsklinikum Leipzig	Leipzig	Germany
Klinikum Mannheim Universitätsklinikum gGmbH	Mannheim	Germany
Klinikum rechts der Isar der Technischen Universität München	München	Germany
Klinikum der Universitat Regensburg	Regensburg	Germany
Attikon University General Hospital	Athens	Greece
University General Hospital of Patras	Pátrai	Greece
ASST Grande Ospedale Metropolitano Niguarda - Presidio Ospedaliero Ospedale Niguarda Ca' Granda	Milan	Italy
Azienda Ospedaliero Universitaria di Parma	Parma	Italy
Ospedale Pediatrico Bambino Gesù	Roma	Italy
Centrum Onkologii im. Marii Sklodowskiej-Curie	Warsaw	Poland
Dolnoslaskie Centrum Transplantacji Komorkowych z Krajowym Bankiem Dawcow Szpiku	Wroclaw	Poland
Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E.	Lisbon	Portugal
Hospital Universitario Marques de Valdecilla	A Coruña	Spain
Hospital de Gran Canaria Doctor Negrin	Las Palmas de Gran Canaria	Spain
Hospital Universitario Puerta de Hierro - Majadahonda	Madrid	Spain
Complejo Asistencial Universitario de Salamanca - H. Clinico	Salamanca	Spain
Hospital Universitario Virgen del Rocio	Seville	Spain
Hospital Clinico Universitario de Valencia	Valencia	Spain
Birmingham Heartlands Hospital	Birmingham	United Kingdom
St James University Hospital	Leeds	United Kingdom
St. James University Hospital	Leeds	United Kingdom
Leicester Royal Infirmary	Leicester	United Kingdom
Manchester Royal Infirmary	Manchester	United Kingdom

+Publications

Results publication: Hudspeth M, Mori S, Nachbaur D, Perez-Simon JA, Stolzel F, Riches M, Wu W, Zhang P, Agarwal S, Yakoub-Agha I. A phase II, prospective, randomized, open-label study of defibrotide added to standard-of-care prophylaxis for the prevention of acute graft-versus-host disease after allogeneic hematopoietic cell transplantation. Haematologica. 2023 Apr 1;108(4):1026-1038. doi: 10.3324/haematol.2022.281471. PMID 36519326

+Study documents

Study Protocol (PDF, 2018-06-19)
Statistical Analysis Plan (PDF, 2020-09-22)