Defibrotide for the Treatment of Severe Hepatic Veno-Occlusive Disease in Hematopoetic Stem Cell Transplant Patients

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00358501
• Collaborator: FDA Office of Orphan Products Development (U.S. Fed)
• Enrollment: 134
• Locations: 25
• Arms: 2
• Duration (Months): 104
• Patients Per Site: 5.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Severe Hepatic Veno-Occlusive Disease	Drug: Defibrotide	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 134 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Defibrotide for the Treatment of Severe Hepatic Veno-Occlusive Disease in Hematopoetic Stem Cell Transplant Patients: A Historically-Controlled, Multi-Center Phase 3 Study to Determine Safety & Efficacy
• Study Start Date: Jul 1, 2006
• Actual Primary Completion Date: Sep 1, 2008
• Actual Study Completion Date: Mar 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Defibrotide Defibrotide treatment	Drug: Defibrotide; Defibrotide 6.25 mg/kg i.v. administered four times a day via 2 hour continuous infusion. Minimum duration 21 days.
No Intervention: Historical Control Historical control group

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. Percentage of Participants With Treatment-Emergent Adverse Events [Through 30 days from the last dose of Defibrotide]

Other Outcome Measures

1. Historical Control Group Adverse Event Information [Through 30 days from the last dose of Defibrotide]

   Historical Control group was not assessed for severity

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Duarte	California	United States
2		Palo Alto	California	United States
3		Denver	Colorado	United States
4		Atlanta	Georgia	United States
5		Chicago	Illinois	United States
6		Maywood	Illinois	United States
7		Indianapolis	Indiana	United States
8		Baltimore	Maryland	United States
9		Boston	Massachusetts	United States
10		Ann Arbor	Michigan	United States
11		Minneapolis	Minnesota	United States
12		Rochester	Minnesota	United States
13		St. Louis	Missouri	United States
14		Omaha	Nebraska	United States
15		Hackensack	New Jersey	United States
16		New York	New York	United States
17		Durham	North Carolina	United States
18		Columbus	Ohio	United States
19		Portland	Oregon	United States
20		Philadelphia	Pennsylvania	United States
21		Houston	Texas	United States
22		Seattle	Washington	United States
23		Vancouver	British Columbia	Canada
24		Toronto	Ontario	Canada
25		Montreal	Quebec	Canada

Sponsors and Collaborators

• Jazz Pharmaceuticals
• FDA Office of Orphan Products Development

Investigators

• Principal Investigator: Paul Richardson, M.D., Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

• Richardson PG, Murakami C, Jin Z, Warren D, Momtaz P, Hoppensteadt D, Elias AD, Antin JH, Soiffer R, Spitzer T, Avigan D, Bearman SI, Martin PL, Kurtzberg J, Vredenburgh J, Chen AR, Arai S, Vogelsang G, McDonald GB, Guinan EC. Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood. 2002 Dec 15;100(13):4337-43. Epub 2002 Aug 1.
• Richardson, Soiffer, Antin, Voss, Jin, Kurtzberget al. Defibrotide (DF) for the Treatment of Severe Veno-Occlusive Disease (VOD) and Multi-System Organ Failure (MOF) Post SCT: Final Results of a Phase II, Multicenter, Randomized Study and Preliminary Analyses of Surrogate Markers and Ultrasound Findings. [abstract]. Blood. 2004;104 (11).

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00358501
• Other Study ID Numbers: 2005-01; NCT00410917
• First Posted: Aug 1, 2006
• Last Update Posted: Jan 30, 2017
• Last Verified: Dec 1, 2016

• Keywords provided by Jazz Pharmaceuticals: Defibrotide; Severe veno occlusive disease; Multi organ failure; Stem cell transplant; Liver; Regimen related toxicity; Day 100 survival
• Additional relevant MeSH terms: Hepatic Veno-Occlusive Disease; Defibrotide

Study Results

Participant Flow

Arm/Group Title	Defibrotide	Historical Control
Arm/Group Description	Defibrotide treatment Defibrotide: Defibrotide 6.25 mg/kg i.v. administered four times a day via 2 hour continuous infusion. Minimum duration 21 days.	The control group was selected from the historical medical charts of patients undergoing HSCT.
Period Title: Overall Study
STARTED	102	32
COMPLETED	102	32
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Defibrotide	Historical Control	Total
Arm/Group Description	Defibrotide treatment Defibrotide: Defibrotide 6.25 mg/kg i.v. administered four times a day via 2 hour continuous infusion. Minimum duration 21 days.	The control group was selected from the historical medical charts of patients undergoing hematopoietic stem cell transplant (HSCT).	Total of all reporting groups
Overall Participants	102	32	134
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26.0 (21.37)	25.1 (20.23)	25.7 (21.03)
Age, Customized (participants) [Number]
≤16 years old	44 43.1%	14 43.8%	58 43.3%
>16 years old	58 56.9%	18 56.3%	76 56.7%
Gender (Count of Participants)
Female	38 37.3%	14 43.8%	52 38.8%
Male	64 62.7%	18 56.3%	82 61.2%
Race/Ethnicity, Customized (participants) [Number]
White	77 75.5%	23 71.9%	100 74.6%
Latino/Latina	10 9.8%	1 3.1%	11 8.2%
African American	6 5.9%	2 6.3%	8 6%
Asian	4 3.9%	2 6.3%	6 4.5%
Native Hawaiian or Other Pacific Islander	1 1%	0 0%	1 0.7%
Other	4 3.9%	4 12.5%	8 6%
Region of Enrollment (participants) [Number]
Canada	6 5.9%	4 12.5%	10 7.5%
United States	93 91.2%	27 84.4%	120 89.6%
Israel	3 2.9%	1 3.1%	4 3%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	53.7 (33.73)	52.6 (30.55)	53.4 (32.89)

Outcome Measures

1. Primary Outcome

Title	Survival at Day+100 Following Hematopoietic Stem Cell Transplant
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Defibrotide	Historical Control
Arm/Group Description	Defibrotide treatment Defibrotide: Defibrotide 6.25 mg/kg i.v. administered four times a day via 2 hour continuous infusion. Minimum duration 21 days.	The control group was selected from the historical medical charts of patients undergoing HSCT.
Measure Participants	102	32
Number (95.1% Confidence Interval) [percentage of participants]	38.2 37.5%	25.0 78.1%

2. Primary Outcome

Title	Complete Response by Day+100 Post Hematopoietic Stem Cell Transplant
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Defibrotide	Historical Control
Arm/Group Description	Defibrotide treatment Defibrotide: Defibrotide 6.25 mg/kg i.v. administered four times a day via 2 hour continuous infusion. Minimum duration 21 days.	The control group was selected from the historical medical charts of patients undergoing HSCT.
Measure Participants	102	32
Number (95.1% Confidence Interval) [percentage of participants]	25.5 25%	12.5 39.1%

3. Secondary Outcome

Title	Survival at Day+180 Post Hematopoietic Stem Cell Transplantation
Description	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

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Defibrotide	Historical Control
Arm/Group Description	Defibrotide treatment Defibrotide: Defibrotide 6.25 mg/kg i.v. administered four times a day via 2 hour continuous infusion. Minimum duration 21 days.	The control group was selected from the historical medical charts of patients undergoing HSCT.
Measure Participants	102	32
Number (95.1% Confidence Interval) [percentage of participants]	32.4 31.8%	25.0 78.1%

4. Secondary Outcome

Title	Percentage of Participants With Treatment-Emergent Adverse Events
Time Frame	Through 30 days from the last dose of Defibrotide

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Defibrotide	Historical Control
Arm/Group Description	Defibrotide treatment Defibrotide: Defibrotide 6.25 mg/kg i.v. administered four times a day via 2 hour continuous infusion. Minimum duration 21 days.	The control group was selected from the historical medical charts of patients undergoing HSCT.
Measure Participants	102	32
Overall TEAEs	97 95.1%	100 312.5%
TEAEs that led to death	64 62.7%	69 215.6%
Treatment-emergent hemorrhage event	64 62.7%	75 234.4%

5. Other Pre-specified Outcome

Title	Historical Control Group Adverse Event Information
Description	Historical Control group was not assessed for severity
Time Frame	Through 30 days from the last dose of Defibrotide

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Historical Control
Arm/Group Description
Measure Participants	32
Total Number of Participants Affected	32
Coagulopathy	5
Anaemia	1
Disseminated intravascular coagulation	1
Thrombocytopenia	1
Haemorrhagic anaemia	1
Tachycardia	14
Bradycardia	6
Cardiac arrest	2
Atrial fibrillation	1
Cardiac failure congestive	2
Sinus tachycardia	1
Cardio-respiratory arrest	1
Ventricular tachycardia	1
Acute myocardial infarction	1
Cardiac failure	1
Cardiac tamponade	1
Dilatation ventricular	1
Pericarditis uraemic	1
Supraventricular tachycardia	1
Systolic dysfunction	1
Tachyarrhythmia	1
Ventricular hypokinesia	1
Adrenal haemorrhage	1
Euthyroid sick syndrome	1
Conjunctival haemorrhage	3
Ocular icterus	1
Scleral haemorrhage	1
Conjunctival hyperaemia	1
Dry eye	1
Eye discharge	1
Eye haemorrhage	1
Eye irritation	1
Lid sulcus deepened	1
Pupils unequal	1
Diarrhoea	12
Vomiting	8
Nausea	10
Abdominal pain	7
Constipation	5
Gastrointestinal haemorrhage	3
Haematemesis	3
Lip haemorrhage	4
Mouth haemorrhage	3
Dyspepsia	1
Haematochezia	3
Melaena	2
Retching	1
Abdominal distension	1
Chapped lips	1
Gastrointestinal hypomotility	2
Gastrointestinal sounds abnormal	1
Upper gastrointestinal haemorrhage	1
Abdominal discomfort	1
Abdominal tenderness	1
Duodenal perforation	1
Duodenal ulcer	1
Dysphagia	1
Epigastric discomfort	1
Gastritis	1
Lip swelling	1
Lower gastrointestinal haemorrhage	1
Oesophagitis	1
Oral disorder	1
Pancreatitis	1
Umbilical hernia	1
Pyrexia	9
Multi-organ failure	3
Oedema peripheral	4
Generalised oedema	8
Hypothermia	5
Oedema	7
Pain	3
Face oedema	3
Asthenia	1
Chills	2
Catheter site erythema	1
Irritability	2
Catheter site swelling	1
Systemic inflammatory response syndrome	1
Thrombosis in device	1
Catheter site related reaction	1
Extravasation	1
Polyserositis	1
Venoocclusive liver disease	2
Hepatic failure	3
Jaundice	3
Hepatorenal syndrome	2
Acute hepatic failure	1
Cholelithiasis	1
Gallbladder disorder	1
Hepatomegaly	1
Portal vein thrombosis	1
Graft versus host disease in skin	5
Graft versus host disease	2
Graft versus host disease in intestine	2
Graft versus host disease in liver	3
Engraftment syndrome	1
Hypogammaglobulinaemia	1
Sepsis	2
Septic shock	2
Bacteraemia	3
Cytomegalovirus infection	1
Pneumonia	1
Candida sepsis	1
Candidiasis	1
Enterococcal infection	1
Catheter site infection	1
Enterococcal sepsis	1
Oral candidiasis	1
Sinusitis	2
Staphylococcal bacteraemia	1
Bacterial infection	1
Clostridium difficile colitis	1
Herpes simplex	1
Nasopharyngitis	1
Osteomyelitis chronic	1
Pneumonia fungal	1
Streptococcal bacteraemia	1
Urinary tract infection enterococcal	1
Vaginal infection	1
Post procedural haemorrhage	1
Contusion	2
Laceration	1
Periorbital haemorrhage	2
Toxicity to various agents	2
Periorbital contusion	1
Endotracheal intubation complication	1
Eschar	1
Eye contusion	1
Scratch	1
Wound haemorrhage	1
Wound secretion	1
Blood urine present	2
Haematocrit decreased	2
Heart rate increased	1
Activated partial thromboplastin time prolonged	1
Ammonia increased	1
Blood urea increased	1
Blood urine	1
Breath sounds abnormal	1
Cardiac murmur	1
Haemoglobin decreased	1
Occult blood positive	1
Prothrombin time prolonged	1
Transaminases increased	1
Urine output decreased	1
Hyperglycaemia	4
Fluid overload	5
Metabolic acidosis	4
Hypovolaemia	2
Acidosis	2
Decreased appetite	1
Hypercalcaemia	1
Hypernatraemia	1
Fluid retention	1
Hypervolaemia	1
Hypoalbuminaemia	1
Lactic acidosis	1
Type 2 diabetes mellitus	1
Back pain	3
Muscle spasms	1
Myalgia	1
Groin pain	1
Limb discomfort	1
Pain in extremity	1
Pain in jaw	1
Convulsion	3
Tremor	4
Cerebral haemorrhage	1
Somnolence	2
Asterixis	1
Lethargy	1
Mental impairment	1
Brain oedema	1
Paralysis	1
Intercranial pressure increased	1
Peripheral nerve palsy	1
Agitation	9
Confusional state	5
Anxiety	4
Mental status change	1
Insomnia	4
Depression	1
Disorientation	4
Paranoia	1
Haematuria	5
Cystitis haemorrhagic	1
Renal failure	1
Bladder spasm	3
Incontinence	2
Anuria	1
Azotaemia	1
Bladder outlet obstruction	1
Chromaturia	1
Pollakiuria	1
Urinary retention	1
Scrotal oedema	2
Oedema genital	1
Perineal pain	1
Vaginal haemorrhage	1
Vulvovaginal erythema	1
Epistaxis	5
Pulmonary alveolar haemorrhage	5
Respiratory failure	4
Pleural effusion	6
Cough	3
Rales	6
Dyspnoea	5
Tachypnoea	2
Apnoea	1
Atelectasis	2
Nasal flaring	3
Oropharyngeal pain	1
Acute respiratory distress syndrome	1
Haemothorax	1
Pneumonia aspiration	2
Respiratory distress	2
Sputum discoloured	1
Wheezing	1
Bronchial haemorrhage	1
Bronchial secretion retention	1
Haemoptysis	1
Hyperventilation	1
Idiopathic pneumonia syndrome	1
Pneumomediastinum	1
Pneumonitis	1
Pulmonary embolism	1
Respiratory acidosis	1
Respiratory disorder	1
Respiratory tract oedema	1
Upper respiratory tract congestion	1
Use of accessory respiratory muscles	1
Petechiae	9
Rash	7
Blister	8
Decubitus ulcer	1
Erythema	3
Pruritus	3
Skin disorder	5
Alopecia	5
Rash erythematous	2
Ecchymosis	1
Skin ulcer	2
Blood blister	1
Skin exfoliation	2
Dermatitis bullous	1
Purpura	1
Rash macular	1
Generalised erythema	1
Hyperhidrosis	1
Rash maculo-papular	1
Skin discolouration	1
Skin hypopigmentation	1
Skin necrosis	1
Hypotension	16
Capillary leak syndrome	2
Ischaemia	1
Pallor	1
Circulatory collapse	1
Hypertension	1
Hypovolaemic shock	1
Shock	1

Adverse Events

Adverse Event Reporting Description	All adverse events data for Historical Control is provided as an Outcome Measure. Historical Control group summary adverse event information is only available without severity and therefore indicated as 0 at risk in the adverse event tables.
Arm/Group Title	Defibrotide		Historical Control
Arm/Group Description	Defibrotide treatment Defibrotide: Defibrotide 6.25 mg/kg i.v. administered four times a day via 2 hour continuous infusion. Minimum duration 21 days.
All Cause Mortality
	Defibrotide		Historical Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Defibrotide		Historical Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	80/102 (78.4%)		0/0 (NaN)
Blood and lymphatic system disorders
Thrombotic thrombocytopenia purpura	3/102 (2.9%)		0/0 (NaN)
Coagulopathy	2/102 (2%)		0/0 (NaN)
Cardiac disorders
Cardiac arrest	2/102 (2%)		0/0 (NaN)
Arrhythmia	1/102 (1%)		0/0 (NaN)
Bradycardia	1/102 (1%)		0/0 (NaN)
Cardiac failure congestive	1/102 (1%)		0/0 (NaN)
Cardio-respiratory arrest	1/102 (1%)		0/0 (NaN)
Cardiopulmonary failure	1/102 (1%)		0/0 (NaN)
Myocardial infarction	1/102 (1%)		0/0 (NaN)
Pericardial effusion	1/102 (1%)		0/0 (NaN)
Congenital, familial and genetic disorders
Tay-Sachs disease	1/102 (1%)		0/0 (NaN)
Gastrointestinal disorders
Gastrointestinal hemorrhage	4/102 (3.9%)		0/0 (NaN)
Colitis	1/102 (1%)		0/0 (NaN)
Diarrhoea	1/102 (1%)		0/0 (NaN)
Haematochezia	1/102 (1%)		0/0 (NaN)
Melaena	1/102 (1%)		0/0 (NaN)
General disorders
Multi-organ failure	15/102 (14.7%)		0/0 (NaN)
Catheter site haemorrhage	2/102 (2%)		0/0 (NaN)
Puncture site haemorrhage	1/102 (1%)		0/0 (NaN)
Pyrexia	1/102 (1%)		0/0 (NaN)
Systematic inflammatory response syndrome	1/102 (1%)		0/0 (NaN)
Hepatobiliary disorders
Venoocclusive liver disease	10/102 (9.8%)		0/0 (NaN)
Hepatic failure	3/102 (2.9%)		0/0 (NaN)
Hepatorenal failure	1/102 (1%)		0/0 (NaN)
Hyperbilirubinaemia	1/102 (1%)		0/0 (NaN)
Liver disease	1/102 (1%)		0/0 (NaN)
Immune system disorders
Graft versus host disease	2/102 (2%)		0/0 (NaN)
Graft versus host disease in skin	1/102 (1%)		0/0 (NaN)
Infections and infestations
Sepsis	6/102 (5.9%)		0/0 (NaN)
Septic shock	3/102 (2.9%)		0/0 (NaN)
Candida sepsis	2/102 (2%)		0/0 (NaN)
Enterococcal infection	2/102 (2%)		0/0 (NaN)
Infection	2/102 (2%)		0/0 (NaN)
Pneumonia	2/102 (2%)		0/0 (NaN)
Adenovirus infection	1/102 (1%)		0/0 (NaN)
Cellulitis	1/102 (1%)		0/0 (NaN)
Enterobacter sepsis	1/102 (1%)		0/0 (NaN)
Enterococcal bacteraemia	1/102 (1%)		0/0 (NaN)
Enterococcal sepsis	1/102 (1%)		0/0 (NaN)
Peritonitis	1/102 (1%)		0/0 (NaN)
Pseudomonal sepsis	1/102 (1%)		0/0 (NaN)
Staphylococcal bacteraemia	1/102 (1%)		0/0 (NaN)
Staphylococcal infection	1/102 (1%)		0/0 (NaN)
Injury, poisoning and procedural complications
Post procedural haemorrhage	1/102 (1%)		0/0 (NaN)
Subdural haemorrhage	1/102 (1%)		0/0 (NaN)
Investigations
Human herpes virus 6 serology	1/102 (1%)		0/0 (NaN)
Oxygen saturation decreased	1/102 (1%)		0/0 (NaN)
Metabolism and nutrition disorders
Hypercalcaemia	1/102 (1%)		0/0 (NaN)
Metabolic acidosis	1/102 (1%)		0/0 (NaN)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia recurrent	2/102 (2%)		0/0 (NaN)
Acute lymphocytic leukaemia recurrent	1/102 (1%)		0/0 (NaN)
Acute myeloid leukaemia	1/102 (1%)		0/0 (NaN)
Leukaemia recurrent	1/102 (1%)		0/0 (NaN)
Nervous system disorders
Intracranial hemorrhage	4/102 (3.9%)		0/0 (NaN)
Cerebral hemorrhage	3/102 (2.9%)		0/0 (NaN)
Convulsion	2/102 (2%)		0/0 (NaN)
Encephalopathy	1/102 (1%)		0/0 (NaN)
Nervous system disorder	1/102 (1%)		0/0 (NaN)
Somnolence	1/102 (1%)		0/0 (NaN)
Subarachnoid haemorrhage	1/102 (1%)		0/0 (NaN)
Syncope	1/102 (1%)		0/0 (NaN)
Psychiatric disorders
Psychotic disorder	1/102 (1%)		0/0 (NaN)
Renal and urinary disorders
Renal failure	4/102 (3.9%)		0/0 (NaN)
Renal impairment	2/102 (2%)		0/0 (NaN)
Cystitis haemorrhagic	1/102 (1%)		0/0 (NaN)
Reproductive system and breast disorders
Pelvic haemorrhage	1/102 (1%)		0/0 (NaN)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	11/102 (10.8%)		0/0 (NaN)
Pulmonary alveolar hemorrhage	10/102 (9.8%)		0/0 (NaN)
Pulmonary hemorrhage	5/102 (4.9%)		0/0 (NaN)
Lung disorder	2/102 (2%)		0/0 (NaN)
Acute respiratory distress syndrome	1/102 (1%)		0/0 (NaN)
Acute respiratory failure	1/102 (1%)		0/0 (NaN)
Epistaxis	1/102 (1%)		0/0 (NaN)
Haemothorax	1/102 (1%)		0/0 (NaN)
Hypoxia	1/102 (1%)		0/0 (NaN)
Pleural effusion	1/102 (1%)		0/0 (NaN)
Pneumothorax	1/102 (1%)		0/0 (NaN)
Pulmonary oedema	1/102 (1%)		0/0 (NaN)
Respiratory arrest	1/102 (1%)		0/0 (NaN)
Thoracic haemorrhage	1/102 (1%)		0/0 (NaN)
Vascular disorders
Hypotension	14/102 (13.7%)		0/0 (NaN)
Haemorrhage	1/102 (1%)		0/0 (NaN)
Ischaemia	1/102 (1%)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Defibrotide		Historical Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	91/102 (89.2%)		0/0 (NaN)
Cardiac disorders
Bradycardia	9/102 (8.8%)		0/0 (NaN)
Tachycardia	10/102 (9.8%)		0/0 (NaN)
Eye disorders
Conjunctival hemorrhage	8/102 (7.8%)		0/0 (NaN)
Gastrointestinal disorders
Diarrhea	24/102 (23.5%)		0/0 (NaN)
Vomiting	20/102 (19.6%)		0/0 (NaN)
Nausea	13/102 (12.7%)		0/0 (NaN)
Constipation	6/102 (5.9%)		0/0 (NaN)
General disorders
Pyrexia	14/102 (13.7%)		0/0 (NaN)
Catheter site hemorrhage	7/102 (6.9%)		0/0 (NaN)
Generalized edema	8/102 (7.8%)		0/0 (NaN)
Oedema peripheral	13/102 (12.7%)		0/0 (NaN)
Injury, poisoning and procedural complications
Post-procedural hemorrhage	6/102 (5.9%)		0/0 (NaN)
Nervous system disorders
Headache	6/102 (5.9%)		0/0 (NaN)
Psychiatric disorders
Mental status change	7/102 (6.9%)		0/0 (NaN)
Agitation	11/102 (10.8%)		0/0 (NaN)
Renal and urinary disorders
Haematuria	10/102 (9.8%)		0/0 (NaN)
Respiratory, thoracic and mediastinal disorders
Epistaxis	13/102 (12.7%)		0/0 (NaN)
Cough	7/102 (6.9%)		0/0 (NaN)
Skin and subcutaneous tissue disorders
Decubitus ulcer	10/102 (9.8%)		0/0 (NaN)
Rash	8/102 (7.8%)		0/0 (NaN)
Blister	6/102 (5.9%)		0/0 (NaN)
Petechiae	6/102 (5.9%)		0/0 (NaN)
Vascular disorders
Hypotension	31/102 (30.4%)		0/0 (NaN)

Limitations/Caveats

Primary endpoint was changed after all patients were treated and current results reflect the final protocol. Adverse event severity was only reported for treatment group as control group was not assessed for severity.

More Information

Certain Agreements

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

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