LPS_DF: Defibrotide in the Human Endotoxemia Model --- an Exploratory Trial Investigating the Effects and the Mechanisms of Defibrotide

• Sponsor: Bernd Jilma (Other)
• Overall Status: Completed
• CT.gov ID: NCT02876601
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arms: 4
• Actual Duration (Months): 9.9
• Patients Per Site Per Month: 2

Study Details

Study Description

Brief Summary

Defibrotide is an anti-inflammatory and anti-coagulatory agent approved for treatment of veno-occlusive disease. Although it has been in clinical use for almost 30 years, the exact mechanism of action has never been fully elucidated. Thus, the effects of defibrotide will be investigated in the human endotoxemia model in order to gather further information on its actions.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers; Endotoxemia	Drug: Defibrotide; Drug: Placebo (0.9% sodium chloride); Drug: Lipopolysaccharide; Drug: Placebo (0.9% sodium chloride bolus)	Phase 4

Detailed Description

Defibrotide (DF) is a highly complex polydisperse mixture of single-stranded phosphodiester oligodeoxyribonucleotides derived from the controlled depolymerization of porcine intestinal mucosal DNA. The entire mode of action remains unknown. Its actions may be summarized to pro-fibrinolytic, anti-inflammatory and anti-coagulatory actions. To better define the mechanisms of Defibrotide the effects of the substance will be investigated in the well-established endotoxemia model. Sixteen healthy volunteers will be randomized to receive LPS±defibrotide/placebo and four subjects will be randomized to receive Placebo± defibrotide/placebo in a single center, randomized, double blind, placebo controlled, two-way crossover trial. Immediately after a 2h infusion of 6,25mg/kg bodyweight defibrotide or placebo a LPS bolus of 2ng/kg bodyweight will be infused. Analyses will be performed by blood sampling at pre-defined time-points.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Subjects will be randomized to receive LPS (n=16) or placebo (n=4) first. In each group they will undergo two study periods (crossover trial): a placebo period and a defibrotide period. The placebo group (n=4) will only be analyzed descriptively.Subjects will be randomized to receive LPS (n=16) or placebo (n=4) first. In each group they will undergo two study periods (crossover trial): a placebo period and a defibrotide period. The placebo group (n=4) will only be analyzed descriptively.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Defibrotide in the Human Endotoxemia Model -- an Exploratory Trial Investigating the Effects and the Mechanisms of Defibrotide
• Actual Study Start Date: Apr 18, 2017
• Actual Primary Completion Date: Feb 12, 2018
• Actual Study Completion Date: Feb 12, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Defibrotide/LPS 2ng/kg lipopolysaccharide period I: 6.25mg/kg bodyweight defibrotide or placebo (0.9% sodium chloride) period II: vice versa 16 healthy volunteers will receive 2ng/kg bodyweight LPS plus Defibrotide or Placebo 4 healthy volunteers will receive 0.9% saline (NO LPS) plus Defibrotide or Placebo	Drug: Defibrotide; 6.25mg/kg bodyweight over 2h infusion; Drug: Lipopolysaccharide; bolus infusion of 2ng/kg bodyweight lps
Placebo Comparator: Placebo/LPS 2ng/kg lipopolysaccharide period I: 6.25mg/kg bodyweight defibrotide or placebo (0.9% sodium chloride) period II: vice versa 16 healthy volunteers will receive 2ng/kg bodyweight LPS plus Defibrotide or Placebo 4 healthy volunteers will receive 0.9% saline (NO LPS) plus Defibrotide or Placebo	Drug: Placebo (0.9% sodium chloride); (0.9% sodium chloride) infusion over 2h infusion; Drug: Lipopolysaccharide; bolus infusion of 2ng/kg bodyweight lps
Other: Defibrotide/Placebo Placebo (0.9% sodium chloride) period I: 6.25mg/kg bodyweight defibrotide or placebo (0.9% sodium chloride) period II: vice versa 16 healthy volunteers will receive 2ng/kg bodyweight LPS plus Defibrotide or Placebo 4 healthy volunteers will receive 0.9% saline (NO LPS) plus Defibrotide or Placebo	Drug: Defibrotide; 6.25mg/kg bodyweight over 2h infusion; Drug: Placebo (0.9% sodium chloride bolus); (0.9% sodium chloride) bolus infusion
Other: Placebo/Placebo Placebo (0.9% sodium chloride) period I: 6.25mg/kg bodyweight defibrotide or placebo (0.9% sodium chloride) period II: vice versa 16 healthy volunteers will receive 2ng/kg bodyweight LPS plus Defibrotide or Placebo 4 healthy volunteers will receive 0.9% saline (NO LPS) plus Defibrotide or Placebo	Drug: Placebo (0.9% sodium chloride); (0.9% sodium chloride) infusion over 2h infusion; Drug: Placebo (0.9% sodium chloride bolus); (0.9% sodium chloride) bolus infusion

Outcome Measures

Primary Outcome Measures

1. Prothrombin Fragments f1+2 [The parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h.]

   Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h. The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison

Secondary Outcome Measures

1. Thrombin-Antithrombin Complexes [This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.]

   Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h. The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison

2. Plasmin-Antiplasmin Complexes [This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, and 6h and AUC was calculated based on these measurements.]

   Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h. The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison

3. Tumor Necrosis Factor (TNF)-Alpha [This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.]

   Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.

4. Tissue-type Plasminogen Activator [This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.]

   Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.

5. Interleukin-6 [This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.]

   Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.

6. E-Selectin [This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.]

   Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.

7. Plasminogen Activator Inhibitor 1 [This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.]

   Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.

8. Von Willebrand Factor Antigen [This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.]

   Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The quantification of von Willebrand Factor is based on reference values and results are in % of "normal". The respective arbitrary unit therefore is %*h.

9. Clotting Time in Thromboelastometry [This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.]

   In this analysis, first of all a ratio of the measurement time point to the baseline was calculated. Thereafter deltas (baeline-ratio) were calculated. With the results an AUC was calculated. The respective arbitrary unit therefore is fold*h.

10. Maximum Lysis in Thromboelastometry [This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h and AUC was calculated based on these measurements.]

    Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• 18 years of age

• <90kg body weight

• Normal findings in medical history and physical examination unless the investigator considers the abnormality to be clinically irrelevant

• Normal laboratory values unless the investigator considers abnormalities to be clinically irrelevant

• Ability to understand the purpose and nature of the study, as well as the associated risks

Exclusion Criteria:

• Intake of any drugs that may interfere with the trial's endpoints or drugs (i.e. platelet inhibitors, anticoagulants, etc.)

• Positive results of HIV or hepatitis virology

• Acute illness with systemic inflammatory reactions

• Known allergies, hypersensitivities or intolerances to any of the used substances

• Acute or recent bleeding episodes, increased risk of bleeding at the discretion of the investigator

• Participation in an LPS trial within 6 weeks of the first study day

• Pregnancy or breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Department of Clinical Pharmacology, Medical University of Vienna	Vienna		Austria	1090

Sponsors and Collaborators

• Bernd Jilma

Investigators

• Principal Investigator: Bernd Jilma, MD, Medical University of Vienna

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 24, 2017

More Information

Publications

None provided.

• Responsible Party: Bernd Jilma, Ao.Univ.Prof.Dr.med, Medical University of Vienna
• ClinicalTrials.gov Identifier: NCT02876601
• Other Study ID Numbers: LPS_DF Version 1.4
• First Posted: Aug 24, 2016
• Last Update Posted: Dec 19, 2019
• Last Verified: Dec 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Bernd Jilma, Ao.Univ.Prof.Dr.med, Medical University of Vienna: Coagulation; Inflammation; Defibrotide; Fibrinolysis
• Additional relevant MeSH terms: Endotoxemia; Defibrotide

Study Results

Participant Flow

Recruitment Details	This was a crossover study. Of 20 healthy volunteers 16 were randomly assigned to receive LPS, while 4 received Placebo only. All participants underwent two study periods: A defibrotide and a placebo period. The system will not let us enter this study design of a crossover study. Only 20 healthy volunteers participated.

Arm/Group Title	LPS+ First Defibrotide, Then Placebo	LPS+ First Placebo, Then Defibrotide	Placebo+ First Defibrotide, Then Placebo	Placebo+ First Placebo, Then Defibrotide
Arm/Group Description	First Intervention: LPS: 2ng/kg bodyweight Defibrotide: 6.25mg/kg bodyweight over 2h infusion Washout for 6 weeks: Second Intervention: LPS: 2ng/kg bodyweight Placebo: 0.9% sodium chloride infusion over 2h infusion	First Intervention: LPS: 2ng/kg bodyweight Placebo: 0.9% sodium chloride infusion over 2h infusion Washout for 6 weeks: Second Intervention: LPS: 2ng/kg bodyweight Defibrotide: 6.25mg/kg bodyweight over 2h infusion	4 healthy volunteers were randomized not to receive LPS. However, they still received Placebo or Defibrotide. This group was included as another control group and to investigate the effects of Defibrotide in vivo. First Intervention: Placebo: bolus infusion of 0.9% sodium chloride solution Defibrotide: 6.25mg/kg bodyweight Defibrotide over 2 hours Washout: 6 weeks Second Intervention: Placebo: bolus infusion of 0.9% sodium chloride solution Placebo: 0.9% sodium chloride solution infusion over 2h	4 healthy volunteers were randomized not to receive LPS. However, they still received Placebo or Defibrotide. This group was included as another control group and to investigate the effects of Defibrotide in vivo. 4 healthy volunteers were randomized not to receive LPS. However, they still received Placebo or Defibrotide. This group was included as another control group and to investigate the effects of Defibrotide in vivo. First Intervention: Placebo: bolus infusion of 0.9% sodium chloride solution Placebo: 0.9% sodium chloride solution infusion over 2h Washout: 6 weeks Second Intervention: Placebo: bolus infusion of 0.9% sodium chloride solution Defibrotide: 6.25mg/kg bodyweight Defibrotide over 2 hours
Period Title: First Intervention (24 Hours)
STARTED	8	8	2	2
COMPLETED	8	8	2	2
NOT COMPLETED	0	0	0	0
Period Title: First Intervention (24 Hours)
STARTED	8	8	2	2
COMPLETED	8	8	1	2
NOT COMPLETED	0	0	1	0
Period Title: First Intervention (24 Hours)
STARTED	8	8	1	2
COMPLETED	8	8	1	2
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	LPS+ First Defibrotide, Then Placebo	LPS+ First Placebo, Then Defibrotide	Placebo+ First Defibrotide, Then Placebo	Placebo+ First Placebo, Then Defibrotide	Total
Arm/Group Description	First Intervention: LPS: 2ng/kg bodyweight Defibrotide: 6.25mg/kg bodyweight over 2h infusion Washout for 6 weeks: Second Intervention: LPS: 2ng/kg bodyweight Placebo: 0.9% sodium chloride infusion over 2h infusion	First Intervention: LPS: 2ng/kg bodyweight Placebo: 0.9% sodium chloride infusion over 2h infusion Washout for 6 weeks: Second Intervention: LPS: 2ng/kg bodyweight Defibrotide: 6.25mg/kg bodyweight over 2h infusion	4 healthy volunteers were randomized not to receive LPS. However, they still received Placebo or Defibrotide. This group was included as another control group and to investigate the effects of Defibrotide in vivo. First Intervention: Placebo: bolus infusion of 0.9% sodium chloride solution Defibrotide: 6.25mg/kg bodyweight Defibrotide over 2 hours Washout: 6 weeks Second Intervention: Placebo: bolus infusion of 0.9% sodium chloride solution Placebo: 0.9% sodium chloride solution infusion over 2h	4 healthy volunteers were randomized not to receive LPS. However, they still received Placebo or Defibrotide. This group was included as another control group and to investigate the effects of Defibrotide in vivo. 4 healthy volunteers were randomized not to receive LPS. However, they still received Placebo or Defibrotide. This group was included as another control group and to investigate the effects of Defibrotide in vivo. First Intervention: Placebo: bolus infusion of 0.9% sodium chloride solution Placebo: 0.9% sodium chloride solution infusion over 2h Washout: 6 weeks Second Intervention: Placebo: bolus infusion of 0.9% sodium chloride solution Defibrotide: 6.25mg/kg bodyweight Defibrotide over 2 hours	Total of all reporting groups
Overall Participants	8	8	2	2	20
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	8 100%	8 100%	2 100%	2 100%	20 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32 (9)	29 (7)	41 (8)	21 (0)	31 (9)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	2 100%	2 10%
Male	8 100%	8 100%	2 100%	0 0%	18 90%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Austria	8 100%	8 100%	2 100%	2 100%	20 100%

Outcome Measures

1. Primary Outcome

Title	Prothrombin Fragments f1+2
Description	Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h. The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison
Time Frame	The parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h.

Outcome Measure Data

Analysis Population Description

The main statistical comparison was done for all subjects receiving LPS (defibrotide vs. placebo). The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison

Arm/Group Title	LPS Plus Defibrotide	LPS Plus Placebo	Placebo Plus Defibrotide	Placebo Plus Placebo
Arm/Group Description	Intervention: 6.25mg/kg bodyweight defibrotide plus 2ng/kg bodyweight LPS bolus infusion	Intervention: 6.25mg/kg bodyweight defibrotide plus 2ng/kg bodyweight LPS bolus infusion	Intervention: placebo infusion (0.9% sodium chloride) plus 2ng/kg bodyweight LPS bolus infusion	Intervention: placebo (0.9% sodium chloride) infusion placebo bolus infusion (0.9% sodium chloride)
Measure Participants	16	16	3	4
Median (Inter-Quartile Range) [fold-change*h]	31.1	34.08	27.41	36.02

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LPS Plus Defibrotide, LPS Plus Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.408
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Thrombin-Antithrombin Complexes
Description	Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h. The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison
Time Frame	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.

Outcome Measure Data

Analysis Population Description

The main statistical comparison was done for all subjects receiving LPS (defibrotide vs. placebo). The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison

Arm/Group Title	LPS Plus Defibrotide	LPS Plus Placebo	Placebo Plus Defibrotide	Placebo Plus Placebo
Arm/Group Description	Intervention: 6.25mg/kg bodyweight defibrotide plus 2ng/kg bodyweight LPS bolus infusion	Intervention: placebo infusion (0.9% sodium chloride) plus 2ng/kg bodyweight LPS bolus infusion	Intervention: 6.25mg/kg bodyweight defibrotide plus placebo bolus infusion (0.9%sodium chloride)	Intervention: placebo infusion (0.9% sodium chloride) plus placebo bolus infusion (0.9% sodium chloride)
Measure Participants	16	16	3	4
Median (Inter-Quartile Range) [fold*h]	23.39	27.4	17.46	21.83

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LPS Plus Defibrotide, LPS Plus Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.148
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Plasmin-Antiplasmin Complexes
Description	Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h. The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison
Time Frame	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, and 6h and AUC was calculated based on these measurements.

Outcome Measure Data

Analysis Population Description

The main statistical comparison was done for all subjects receiving LPS (defibrotide vs. placebo). The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison

Arm/Group Title	LPS Plus Defibrotide	LPS/Placebo	Placebo Plus Defibrotide	Placebo Plus Placebo
Arm/Group Description	Intervention: 6.25mg/kg bodyweight defibrotide and 2ng/kg bodyweight LPS bolus	Intervention: placebo infusion (0.9% sodium chloride) and 2ng/kg bodyweight LPS bolus	Intervention: 6.25mg/kg bodyweight defibrotide and Placebo bolus (0.9% sodium chloride)	Intervention: placebo infusion (0.9% sodium chloride) and placebo bolus infusion (0.9% sodium chloride)
Measure Participants	16	16	3	4
Median (Inter-Quartile Range) [fold*h]	11.8	9.99	7	7.12

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LPS Plus Defibrotide, LPS Plus Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.039
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	Tumor Necrosis Factor (TNF)-Alpha
Description	Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.
Time Frame	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.

Outcome Measure Data

Analysis Population Description

The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison

Arm/Group Title	LPS Plus Defibrotide	LPS Plus Placebo	Placebo Plus Defibrotide	Placebo Plus Placebo
Arm/Group Description	Intervention: 6.25mg/kg bodyweight defibrotide plus 2ng/kg lipopolysaccharide bolus infusion	Intervention: 6.25mg/kg bodyweight defibrotide plus placebo bolus infusion (0.9% sodium chloride)	Intervention: 6.25mg/kg bodyweight defibrotide plus Placebo infusion (0.9% sodium chloride	Intervention: placebo infusion (0.9% sodium chloride) plus placebo bolus infusion (0.9% sodium chloride)
Measure Participants	16	16	3	4
Median (Inter-Quartile Range) [fold*h]	286	326	28.08	21.01

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LPS Plus Defibrotide, LPS Plus Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.642
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Tissue-type Plasminogen Activator
Description	Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.
Time Frame	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.

Outcome Measure Data

Analysis Population Description

The main statistical comparison was done for all subjects receiving LPS (defibrotide vs. placebo). The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison

Arm/Group Title	LPS Plus Defibrotide	LPS Plus Placebo	Placebo Plus Defibrotide	Placebo Plus Placebo
Arm/Group Description	Intervention: 6.25mg/kg bodyweight defibrotide plus 2ng/kg bodyweight lipopolysaccharide	Intervention: Placebo infusion (0.9% sodium chloride) plus 2ng/kg bodyweight LPS	Intervention: placebo bolus (0.9% sodium chloride) plus 6.25mg/kg bodyweight defibrotide	Intervention: placebo bolus (0.9% sodium chloride) plus placebo (0.9% sodium chloride) infusion
Measure Participants	16	16	3	4
Median (Inter-Quartile Range) [fold*h]	21.8	17	20.57	23.54

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LPS Plus Defibrotide, LPS Plus Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.026
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Interleukin-6
Description	Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.
Time Frame	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.

Outcome Measure Data

Analysis Population Description

The main statistical comparison was done for all subjects receiving LPS (defibrotide vs. placebo). The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison

Arm/Group Title	LPS Plus Defibrotide	LPS Plus Placebo	Placebo Plus Defibrotide	Placebo Plus Placebo
Arm/Group Description	Intervention: 6.25mg/kg bodyweight defibrotide plus infusionbolus infusion of 2ng/kg bodyweight LPS	Intervention: Bolus infusion of 2ng/kg bodyweight LPS plus Placebo (0.9% sodium chloride)	Intervention: 6.25mg/kg bodyweight Defibrotide infusion plus Placebo (0.9% sodium chloride)	Intervention: Placebo (0.9% sodium chloride) bolus infusion plus placebo (0.9% sodium chloride) infusion
Measure Participants	16	16	3	4
Median (Inter-Quartile Range) [fold*h]	1543	1144	35	31

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LPS Plus Defibrotide, LPS Plus Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.326
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

7. Secondary Outcome

Title	E-Selectin
Description	Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.
Time Frame	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.

Outcome Measure Data

Analysis Population Description

The main statistical comparison was done for all subjects receiving LPS (defibrotide vs. placebo). The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison

Arm/Group Title	LPS Plus Defibrotide	LPS Plus Placebo	Placebo Plus Defibrotide	Placebo Plus Placebo
Arm/Group Description	Intervention: Defibrotide 6.25mg/kg infusion plus bolus infusion of 2ng/kg bodyweight LPS	Intervention: placebo (0.9% sodium chloride) infusion plus 2ng/kg bodyweight LPS bolus infusion	Intervention: 6.25mg/kg bodyweight defibrotide infusion plus placebo (0.9% sodium chloride) bolus infusion	Intervention: placebo infusion (0.9% sodium chloride) plus placebo bolus infusion (0.9% sodium chloride)
Measure Participants	16	16	3	4
Median (Inter-Quartile Range) [fold*h]	35	33	21	41

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LPS Plus Defibrotide, LPS Plus Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.796
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

8. Secondary Outcome

Title	Plasminogen Activator Inhibitor 1
Description	Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.
Time Frame	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.

Outcome Measure Data

Analysis Population Description

The main statistical comparison was done for all subjects receiving LPS (defibrotide vs. placebo). The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison

Arm/Group Title	LPS Plus Defibrotide	LPS Plus Placebo	Placebo Plus Defibrotide	Placebo Plus Placebo
Arm/Group Description	Intervention: 6.25mg/kg bodyweight defibrotide infusion plus 2ng/kg LPS bolus infusion	Intervention: placebo (0.9% sodium chloride) infusion plus 2ng/kg bodyweight LPS	Intervention: 6.25mg/kg bodyweight defibrotide plus placebo (0.9% sodium chloride) infusion	Intervention: placebo (0.9% sodium chloride) infusion plus placebo (0.9% sodium chloride) bolus infusion
Measure Participants	16	16	3	4
Median (Inter-Quartile Range) [fold*h]	216	477	25	24.86

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LPS Plus Defibrotide, LPS Plus Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.918
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

9. Secondary Outcome

Title	Von Willebrand Factor Antigen
Description	Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The quantification of von Willebrand Factor is based on reference values and results are in % of "normal". The respective arbitrary unit therefore is %*h.
Time Frame	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.

Outcome Measure Data

Analysis Population Description

The main statistical comparison was done for all subjects receiving LPS (defibrotide vs. placebo). The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison.

Arm/Group Title	LPS Plus Defibrotide	LPS Plus Placebo	Placebo Plus Defibrotie	Placebo Plus Placebo
Arm/Group Description	Intervention: 6.25mg/kg bodyweight defibrotide plus 2ng/kg bodyweight LPS bolus infusion	Intervention: Placebo infusion (0.9% sodium chloride) plus 2ng/kg bodyweight LPS bolus infusion	Intervention: 6.25mg/kg bodyweight defibrotide plus placebo bolus infusion (0.9% sodium chloride solution)	Intervention: Placebo (0.9% sodium chloride solution) infusion plus placebo bolus infusion (0.9% sodium chloride)
Measure Participants	16	16	3	4
Median (Inter-Quartile Range) [%*h]	54	53	27	26

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LPS Plus Defibrotide, LPS Plus Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.877
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

10. Secondary Outcome

Title	Clotting Time in Thromboelastometry
Description	In this analysis, first of all a ratio of the measurement time point to the baseline was calculated. Thereafter deltas (baeline-ratio) were calculated. With the results an AUC was calculated. The respective arbitrary unit therefore is fold*h.
Time Frame	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.

Outcome Measure Data

Analysis Population Description

The main statistical comparison was done for all subjects receiving LPS (defibrotide vs. placebo). The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison.

Arm/Group Title	LPS Plus Defibrotide	LPS Plus Placebo	Placebo Plus Defibrotide	Placebo Plus Placebo
Arm/Group Description	Intervention: 6.25mg/kg bodyweight LPS plus bolus infusion of 2ng/kg bodyweight LPS	Intervention: placebo infusion (0.9% sodium chloride solution) plus bolus infusion of 2ng/kg bodyweight LPS	Intervention: 6.25mg/kg bodyweight defibrotide infusion plus placebo (0.9% sodium chloride solution) bolus infusion	Intervention: placebo (0.9%sodium chloride solution) infusion plus placebo bolus infusion (0.9% sodium chloride solution)
Measure Participants	16	16	3	4
Median (Inter-Quartile Range) [fold*h]	1.12	1.12	-0.2	2.14

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LPS Plus Defibrotide, LPS Plus Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.423
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

11. Secondary Outcome

Title	Maximum Lysis in Thromboelastometry
Description	Based on the changes from baseline an area-under the concentration-time curve will be calculated and will be compared between the placebo and the verum phase within each subject. The respective arbitrary unit therefore is fold*h.
Time Frame	This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h and AUC was calculated based on these measurements.

Outcome Measure Data

Analysis Population Description

The main statistical comparison was done for all subjects receiving LPS (defibrotide vs. placebo). The "placebo period" (4 subjects who did not receive lipopolysaccharide) was only included for a descriptive comparison, but not for statistical comparison.

Arm/Group Title	LPS Plus Defibrotide	LPS Plus Placebo	Placebo Plus Defibrotide	Placebo Plus Placebo
Arm/Group Description	Intervention: 6.25mg/kg bodyweight infusion plus 2ng/kg bodyweight LPS bolus infusion	Intervention: placebo infusion (0.9% sodium chloride infusion) plus 2ng/kg bodyweight LPS bolus infusion	Intervention: 6.25mg/kg bodyweight infusion plus placebo (0.9% sodium chloride solution) bolus infusion	Intervention: placebo (0.9% sodium chloride) infusion plus placebo (0.9% sodium chloride) bolus infusion
Measure Participants	16	16	3	4
Median (Inter-Quartile Range) [fold*h]	7.9	7.7	6.84	6.85

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LPS Plus Defibrotide, LPS Plus Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.938
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	For the individual subject, adverse events were assessed during every study visit (screening, study day1, study day 2, follow up) during the whole study. The whole study period lastet for a minimum of 8 weeks, but could be longer for individual subjects (washout period was a minimum of 6 weeks). The respective time frame could therefore differ between the individual subjects but was a minimum of 8 weeks.
Arm/Group Title	Defibrotide Plus LPS		Placebo Plus LPS		Defibrotide Plus Placebo		Placebo/Placebo
Arm/Group Description	Intervention: 6.25mg/kg bodyweight defibrotide infusion plus 2ng/kg bodyweight LPS infusion		Intervention: placebo infusion (0.9% sodium chloride solution) plus 2ng/kg bodyweight LPS infusion		Intervention: 6.25mg/kg bodyweight defibrotide infusion plus placebo bolus infusion (0.9% sodium chloride solution)		Intervention: placebo infusion (0.9% sodium chloride solution) plus placebo bolus infusion (0.9% sodium chloride solution)
All Cause Mortality
	Defibrotide Plus LPS		Placebo Plus LPS		Defibrotide Plus Placebo		Placebo/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)		0/3 (0%)		0/4 (0%)
Serious Adverse Events
	Defibrotide Plus LPS		Placebo Plus LPS		Defibrotide Plus Placebo		Placebo/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)		0/3 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Defibrotide Plus LPS		Placebo Plus LPS		Defibrotide Plus Placebo		Placebo/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/16 (81.3%)		15/16 (93.8%)		1/3 (33.3%)		1/4 (25%)
General disorders
Flu-like Symptoms	6/16 (37.5%)	6	6/16 (37.5%)	6	0/3 (0%)	0	0/4 (0%)	0
Arthralgia	2/16 (12.5%)	2	7/16 (43.8%)	7	0/3 (0%)	0	0/4 (0%)	0
Chills	3/16 (18.8%)	3	6/16 (37.5%)	6	0/3 (0%)	0	0/4 (0%)	0
Impaired Concentration	0/16 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0	0/4 (0%)	0
Fatigue	0/16 (0%)	0	1/16 (6.3%)	1	0/3 (0%)	0	0/4 (0%)	0
Precollapse	1/16 (6.3%)	1	0/16 (0%)	0	0/3 (0%)	0	0/4 (0%)	0
Dizziness	1/16 (6.3%)	1	0/16 (0%)	0	0/3 (0%)	0	0/4 (0%)	0
Nausea	2/16 (12.5%)	2	1/16 (6.3%)	1	0/3 (0%)	0	0/4 (0%)	0
Nervous system disorders
Headache	13/16 (81.3%)	13	11/16 (68.8%)	11	0/3 (0%)	0	1/4 (25%)	1
Vertigo	1/16 (6.3%)	1	0/16 (0%)	0	0/3 (0%)	0	0/4 (0%)	0
Skin and subcutaneous tissue disorders
Urticarial rash	0/16 (0%)	0	0/16 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.