Severe Hepatic Veno-Occlusive Disease
Conditions
Keywords
Defibrotide, Severe veno occlusive disease, Multi organ failure, Stem cell transplant, Liver, Regimen related toxicity, Day 100 survival
Brief summary
The purpose of this study is to (1) demonstrate the efficacy and safety (toxicity) of 25 mg/kg/day of Defibrotide in patients with severe veno-occlusive disease (sVOD) and (2) evaluate serum and endothelial markers of veno-occlusive disease (VOD) through the analysis of blood samples.
Detailed description
This is a historically-controlled, multicenter, open label Phase 3 study to determine the safety and efficacy of 25 mg/kg/day of Defibrotide (DF) for the treatment of severe VOD in hematopoietic stem cell transplantation (HSCT) patients. In this study, the term severe VOD is defined as those patients who meet the Baltimore diagnostic criteria for VOD (total bilirubin \>/= 2.0 mg/dL plus two of the following: ascites, \>/=5% weight gain and hepatomegaly), who also have multi-organ failure (i.e., pulmonary and/or renal dysfunction). This represents a group of patients in whom mortality at Day+100 has been estimated to be \>80%. Comparisons: The primary parameter is Complete Response at 100 days following stem cell transplant, utilizing historical controls as a comparator. The historical control database will be generated through a retrospective medical chart review performed at participating centers; the survival outcome of patients who would otherwise have met eligibility criteria for this trial will be compared to the survival observed in patients prospectively treated with Defibrotide. Secondary parameters include survival rate at 100 days and 6 months post stem cell transplantation (SCT), and special studies of endothelial and serum markers for VOD. This study will assess safety of the dose and schedule in this setting.
Interventions
DRUGDefibrotide
Defibrotide 6.25 mg/kg i.v. administered four times a day via 2 hour continuous infusion. Minimum duration 21 days.
Sponsors
FDA Office of Orphan Products Development
Jazz Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of VOD, defined by jaundice (bilirubin \>/= 2 mg/dL) and at least 2 of the following clinical findings, by Day+21 post stem cell transplant: ascites; weight gain \>/= 5% above baseline weight; hepatomegaly. * Severe VOD, defined as VOD with multi-organ failure, i.e., presence of one or both of the following, by Day+28 post stem cell transplant: renal or pulmonary dysfunction. * Provide voluntary written informed consent.
Exclusion criteria
* Pre-existing (prior to SCT) cirrhosis * An alternative diagnosis for weight gain, ascites and jaundice * Graft-versus-host disease (GVHD) grade B or higher involving liver or gut or grade C or higher involving skin * Prior solid organ transplant * Dependent on dialysis prior to and/or at the time of SCT * Dependent on oxygen supplementation prior to SCT * Significant acute bleeding or hemodynamic instability * Requirement for the use of any medications that increase risk of hemorrhage will be excluded from the treatment group
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Survival at Day+100 Following Hematopoietic Stem Cell Transplant | Day+100 post hematopoietic stem cell transplant | The 95.1% CI instead of 95% CI is used for the final analysis to provide a small adjustment for the fact that an interim analysis was performed. |
| Complete Response by Day+100 Post Hematopoietic Stem Cell Transplant | Day+100 post hematopoietic stem cell transplant | The 95.1% CI instead of 95% CI is used for the final analysis to provide a small adjustment for the fact that an interim analysis was performed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Survival at Day+180 Post Hematopoietic Stem Cell Transplantation | 180 days post hematopoietic stem cell transplant | The 95.1% CI instead of 95% CI is used for the final analysis to provide a small adjustment for the fact that an interim analysis was performed. |
| Percentage of Participants With Treatment-Emergent Adverse Events | Through 30 days from the last dose of Defibrotide | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Historical Control Group Adverse Event Information | Through 30 days from the last dose of Defibrotide | Historical Control group was not assessed for severity |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Defibrotide Defibrotide treatment
Defibrotide: Defibrotide 6.25 mg/kg i.v. administered four times a day via 2 hour continuous infusion. Minimum duration 21 days. | 102 |
| Historical Control The control group was selected from the historical medical charts of patients undergoing hematopoietic stem cell transplant (HSCT). | 32 |
| Total | 134 |
Baseline characteristics
| Characteristic | Defibrotide | Historical Control | Total |
|---|---|---|---|
| Age, Continuous | 26.0 years STANDARD_DEVIATION 21.37 | 25.1 years STANDARD_DEVIATION 20.23 | 25.7 years STANDARD_DEVIATION 21.03 |
| Age, Customized ≤16 years old | 44 participants | 14 participants | 58 participants |
| Age, Customized >16 years old | 58 participants | 18 participants | 76 participants |
| Gender Female | 38 Participants | 14 Participants | 52 Participants |
| Gender Male | 64 Participants | 18 Participants | 82 Participants |
| Race/Ethnicity, Customized African American | 6 participants | 2 participants | 8 participants |
| Race/Ethnicity, Customized Asian | 4 participants | 2 participants | 6 participants |
| Race/Ethnicity, Customized Latino/Latina | 10 participants | 1 participants | 11 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Other | 4 participants | 4 participants | 8 participants |
| Race/Ethnicity, Customized White | 77 participants | 23 participants | 100 participants |
| Region of Enrollment Canada | 6 participants | 4 participants | 10 participants |
| Region of Enrollment Israel | 3 participants | 1 participants | 4 participants |
| Region of Enrollment United States | 93 participants | 27 participants | 120 participants |
| Weight | 53.7 kg STANDARD_DEVIATION 33.73 | 52.6 kg STANDARD_DEVIATION 30.55 | 53.4 kg STANDARD_DEVIATION 32.89 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 91 / 102 | 0 / 0 |
| serious Total, serious adverse events | 80 / 102 | 0 / 0 |
Outcome results
Primary
Complete Response by Day+100 Post Hematopoietic Stem Cell Transplant
The 95.1% CI instead of 95% CI is used for the final analysis to provide a small adjustment for the fact that an interim analysis was performed.
Time frame: Day+100 post hematopoietic stem cell transplant
Population: Intent-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Defibrotide | Complete Response by Day+100 Post Hematopoietic Stem Cell Transplant | 25.5 percentage of participants |
| Historical Control | Complete Response by Day+100 Post Hematopoietic Stem Cell Transplant | 12.5 percentage of participants |
Primary
Survival at Day+100 Following Hematopoietic Stem Cell Transplant
The 95.1% CI instead of 95% CI is used for the final analysis to provide a small adjustment for the fact that an interim analysis was performed.
Time frame: Day+100 post hematopoietic stem cell transplant
Population: Intent-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Defibrotide | Survival at Day+100 Following Hematopoietic Stem Cell Transplant | 38.2 percentage of participants |
| Historical Control | Survival at Day+100 Following Hematopoietic Stem Cell Transplant | 25.0 percentage of participants |
Secondary
Percentage of Participants With Treatment-Emergent Adverse Events
Time frame: Through 30 days from the last dose of Defibrotide
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Defibrotide | Percentage of Participants With Treatment-Emergent Adverse Events | Overall TEAEs | 97 percentage of participants |
| Defibrotide | Percentage of Participants With Treatment-Emergent Adverse Events | TEAEs that led to death | 64 percentage of participants |
| Defibrotide | Percentage of Participants With Treatment-Emergent Adverse Events | Treatment-emergent hemorrhage event | 64 percentage of participants |
| Historical Control | Percentage of Participants With Treatment-Emergent Adverse Events | Overall TEAEs | 100 percentage of participants |
| Historical Control | Percentage of Participants With Treatment-Emergent Adverse Events | TEAEs that led to death | 69 percentage of participants |
| Historical Control | Percentage of Participants With Treatment-Emergent Adverse Events | Treatment-emergent hemorrhage event | 75 percentage of participants |
Secondary
Survival at Day+180 Post Hematopoietic Stem Cell Transplantation
The 95.1% CI instead of 95% CI is used for the final analysis to provide a small adjustment for the fact that an interim analysis was performed.
Time frame: 180 days post hematopoietic stem cell transplant
Population: Intent-to-Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Defibrotide | Survival at Day+180 Post Hematopoietic Stem Cell Transplantation | 32.4 percentage of participants |
| Historical Control | Survival at Day+180 Post Hematopoietic Stem Cell Transplantation | 25.0 percentage of participants |
Other Pre-specified
Historical Control Group Adverse Event Information
Historical Control group was not assessed for severity
Time frame: Through 30 days from the last dose of Defibrotide
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Defibrotide | Historical Control Group Adverse Event Information | Blister | 8 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Decubitus ulcer | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Erythema | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pruritus | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Skin disorder | 5 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Alopecia | 5 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Rash erythematous | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Ecchymosis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Skin ulcer | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Blood blister | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Skin exfoliation | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Dermatitis bullous | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Purpura | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Rash macular | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Generalised erythema | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Hyperhidrosis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Rash maculo-papular | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Skin discolouration | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Skin hypopigmentation | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Skin necrosis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Hypotension | 16 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Capillary leak syndrome | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Ischaemia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pallor | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Circulatory collapse | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Hypertension | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Hypovolaemic shock | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Shock | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Diarrhoea | 12 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Vomiting | 8 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Total Number of Participants Affected | 32 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Coagulopathy | 5 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Anaemia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Disseminated intravascular coagulation | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Thrombocytopenia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Haemorrhagic anaemia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Tachycardia | 14 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Bradycardia | 6 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Cardiac arrest | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Atrial fibrillation | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Cardiac failure congestive | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Sinus tachycardia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Cardio-respiratory arrest | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Ventricular tachycardia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Acute myocardial infarction | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Cardiac failure | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Cardiac tamponade | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Dilatation ventricular | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pericarditis uraemic | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Supraventricular tachycardia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Systolic dysfunction | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Tachyarrhythmia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Ventricular hypokinesia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Adrenal haemorrhage | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Euthyroid sick syndrome | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Conjunctival haemorrhage | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Ocular icterus | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Scleral haemorrhage | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Conjunctival hyperaemia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Dry eye | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Eye discharge | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Eye haemorrhage | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Eye irritation | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Lid sulcus deepened | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pupils unequal | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Nausea | 10 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Abdominal pain | 7 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Constipation | 5 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Gastrointestinal haemorrhage | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Haematemesis | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Lip haemorrhage | 4 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Mouth haemorrhage | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Dyspepsia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Haematochezia | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Melaena | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Retching | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Abdominal distension | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Chapped lips | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Gastrointestinal hypomotility | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Gastrointestinal sounds abnormal | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Upper gastrointestinal haemorrhage | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Abdominal discomfort | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Abdominal tenderness | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Duodenal perforation | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Duodenal ulcer | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Dysphagia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Epigastric discomfort | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Gastritis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Lip swelling | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Lower gastrointestinal haemorrhage | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Oesophagitis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Oral disorder | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pancreatitis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Umbilical hernia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pyrexia | 9 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Multi-organ failure | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Oedema peripheral | 4 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Generalised oedema | 8 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Hypothermia | 5 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Oedema | 7 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pain | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Face oedema | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Asthenia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Chills | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Catheter site erythema | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Irritability | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Catheter site swelling | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Systemic inflammatory response syndrome | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Thrombosis in device | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Catheter site related reaction | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Extravasation | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Polyserositis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Venoocclusive liver disease | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Hepatic failure | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Jaundice | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Hepatorenal syndrome | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Acute hepatic failure | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Cholelithiasis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Gallbladder disorder | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Hepatomegaly | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Portal vein thrombosis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Graft versus host disease in skin | 5 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Graft versus host disease | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Graft versus host disease in intestine | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Graft versus host disease in liver | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Engraftment syndrome | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Hypogammaglobulinaemia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Sepsis | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Septic shock | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Bacteraemia | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Cytomegalovirus infection | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pneumonia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Candida sepsis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Candidiasis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Enterococcal infection | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Catheter site infection | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Enterococcal sepsis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Oral candidiasis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Sinusitis | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Staphylococcal bacteraemia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Bacterial infection | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Clostridium difficile colitis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Herpes simplex | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Nasopharyngitis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Osteomyelitis chronic | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pneumonia fungal | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Streptococcal bacteraemia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Urinary tract infection enterococcal | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Vaginal infection | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Post procedural haemorrhage | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Contusion | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Laceration | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Periorbital haemorrhage | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Toxicity to various agents | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Periorbital contusion | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Endotracheal intubation complication | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Eschar | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Eye contusion | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Scratch | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Wound haemorrhage | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Wound secretion | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Blood urine present | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Haematocrit decreased | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Heart rate increased | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Activated partial thromboplastin time prolonged | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Ammonia increased | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Blood urea increased | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Blood urine | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Breath sounds abnormal | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Cardiac murmur | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Haemoglobin decreased | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Occult blood positive | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Prothrombin time prolonged | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Transaminases increased | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Urine output decreased | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Hyperglycaemia | 4 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Fluid overload | 5 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Metabolic acidosis | 4 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Hypovolaemia | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Acidosis | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Decreased appetite | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Hypercalcaemia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Hypernatraemia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Fluid retention | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Hypervolaemia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Hypoalbuminaemia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Lactic acidosis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Type 2 diabetes mellitus | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Back pain | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Muscle spasms | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Myalgia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Groin pain | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Limb discomfort | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pain in extremity | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pain in jaw | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Convulsion | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Tremor | 4 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Cerebral haemorrhage | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Somnolence | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Asterixis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Lethargy | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Mental impairment | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Brain oedema | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Paralysis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Intercranial pressure increased | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Peripheral nerve palsy | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Agitation | 9 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Confusional state | 5 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Anxiety | 4 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Mental status change | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Insomnia | 4 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Depression | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Disorientation | 4 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Paranoia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Haematuria | 5 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Cystitis haemorrhagic | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Renal failure | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Bladder spasm | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Incontinence | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Anuria | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Azotaemia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Bladder outlet obstruction | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Chromaturia | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pollakiuria | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Urinary retention | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Scrotal oedema | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Oedema genital | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Perineal pain | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Vaginal haemorrhage | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Vulvovaginal erythema | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Epistaxis | 5 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pulmonary alveolar haemorrhage | 5 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Respiratory failure | 4 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pleural effusion | 6 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Cough | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Rales | 6 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Dyspnoea | 5 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Tachypnoea | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Apnoea | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Atelectasis | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Nasal flaring | 3 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Oropharyngeal pain | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Acute respiratory distress syndrome | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Haemothorax | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pneumonia aspiration | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Respiratory distress | 2 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Sputum discoloured | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Wheezing | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Bronchial haemorrhage | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Bronchial secretion retention | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Haemoptysis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Hyperventilation | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Idiopathic pneumonia syndrome | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pneumomediastinum | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pneumonitis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Pulmonary embolism | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Respiratory acidosis | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Respiratory disorder | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Respiratory tract oedema | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Upper respiratory tract congestion | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Use of accessory respiratory muscles | 1 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Petechiae | 9 Number of patients |
| Defibrotide | Historical Control Group Adverse Event Information | Rash | 7 Number of patients |