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

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

Status
Completed
Phases
Phase 4
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT02876601
Acronym
LPS_DF
Enrollment
20
Registered
2016-08-24
Start date
2017-04-18
Completion date
2018-02-12
Last updated
2019-12-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy Volunteers, Endotoxemia

Keywords

Coagulation, Inflammation, Defibrotide, Fibrinolysis

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.

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.

Interventions

DRUGDefibrotide

6.25mg/kg bodyweight over 2h infusion

DRUGPlacebo (0.9% sodium chloride)

(0.9% sodium chloride) infusion over 2h infusion

DRUGLipopolysaccharide

bolus infusion of 2ng/kg bodyweight lps

DRUGPlacebo (0.9% sodium chloride bolus)

(0.9% sodium chloride) bolus infusion

Sponsors

Bernd Jilma
Lead SponsorOTHER

Study design

Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

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.

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
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

Design outcomes

Primary

MeasureTime frameDescription
Prothrombin Fragments f1+2The 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

MeasureTime frameDescription
Plasmin-Antiplasmin ComplexesThis 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
Tumor Necrosis Factor (TNF)-AlphaThis 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.
Tissue-type Plasminogen ActivatorThis 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.
Interleukin-6This 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.
Thrombin-Antithrombin ComplexesThis 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
Plasminogen Activator Inhibitor 1This 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.
Von Willebrand Factor AntigenThis 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.
Clotting Time in ThromboelastometryThis 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.
Maximum Lysis in ThromboelastometryThis 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.
E-SelectinThis 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.

Countries

Austria

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.

Participants by arm

ArmCount
LPS+ First Defibrotide, Then Placebo
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
8
LPS+ First Placebo, Then Defibrotide
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
8
Placebo+ First Defibrotide, Then Placebo
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
2
Placebo+ First Placebo, Then Defibrotide
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
2
Total20

Withdrawals & dropouts

PeriodReasonFG000FG001FG002FG003
Washout (Minimum of 6 Weeks)unforeseen unavailability0010

Baseline characteristics

CharacteristicLPS+ First Placebo, Then DefibrotidePlacebo+ First Defibrotide, Then PlaceboPlacebo+ First Placebo, Then DefibrotideLPS+ First Defibrotide, Then PlaceboTotal
Age, Categorical
<=18 years
0 Participants0 Participants0 Participants0 Participants0 Participants
Age, Categorical
>=65 years
0 Participants0 Participants0 Participants0 Participants0 Participants
Age, Categorical
Between 18 and 65 years
8 Participants2 Participants2 Participants8 Participants20 Participants
Age, Continuous29 years
STANDARD_DEVIATION 7
41 years
STANDARD_DEVIATION 8
21 years
STANDARD_DEVIATION 0
32 years
STANDARD_DEVIATION 9
31 years
STANDARD_DEVIATION 9
Race and Ethnicity Not Collected————0 Participants
Region of Enrollment
Austria
8 participants2 participants2 participants8 participants20 participants
Sex: Female, Male
Female
0 Participants0 Participants2 Participants0 Participants2 Participants
Sex: Female, Male
Male
8 Participants2 Participants0 Participants8 Participants18 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
EG003
affected / at risk
deaths
Total, all-cause mortality
0 / 160 / 160 / 30 / 4
other
Total, other adverse events
13 / 1615 / 161 / 31 / 4
serious
Total, serious adverse events
0 / 160 / 160 / 30 / 4

Outcome results

Primary

Prothrombin Fragments f1+2

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.

Population: 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

ArmMeasureValue (MEDIAN)
LPS Plus DefibrotideProthrombin Fragments f1+231.1 fold-change*h
LPS Plus PlaceboProthrombin Fragments f1+234.08 fold-change*h
Placebo Plus DefibrotideProthrombin Fragments f1+227.41 fold-change*h
Placebo Plus PlaceboProthrombin Fragments f1+236.02 fold-change*h
p-value: 0.408Wilcoxon (Mann-Whitney)
Secondary

Clotting Time in Thromboelastometry

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.

Population: 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.

ArmMeasureValue (MEDIAN)
LPS Plus DefibrotideClotting Time in Thromboelastometry1.12 fold*h
LPS Plus PlaceboClotting Time in Thromboelastometry1.12 fold*h
Placebo Plus DefibrotideClotting Time in Thromboelastometry-0.2 fold*h
Placebo Plus PlaceboClotting Time in Thromboelastometry2.14 fold*h
p-value: 0.423Wilcoxon (Mann-Whitney)
Secondary

E-Selectin

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.

Population: 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

ArmMeasureValue (MEDIAN)
LPS Plus DefibrotideE-Selectin35 fold*h
LPS Plus PlaceboE-Selectin33 fold*h
Placebo Plus DefibrotideE-Selectin21 fold*h
Placebo Plus PlaceboE-Selectin41 fold*h
p-value: 0.796Wilcoxon (Mann-Whitney)
Secondary

Interleukin-6

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.

Population: 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

ArmMeasureValue (MEDIAN)
LPS Plus DefibrotideInterleukin-61543 fold*h
LPS Plus PlaceboInterleukin-61144 fold*h
Placebo Plus DefibrotideInterleukin-635 fold*h
Placebo Plus PlaceboInterleukin-631 fold*h
p-value: 0.326Wilcoxon (Mann-Whitney)
Secondary

Maximum Lysis in Thromboelastometry

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.

Population: 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.

ArmMeasureValue (MEDIAN)
LPS Plus DefibrotideMaximum Lysis in Thromboelastometry7.9 fold*h
LPS Plus PlaceboMaximum Lysis in Thromboelastometry7.7 fold*h
Placebo Plus DefibrotideMaximum Lysis in Thromboelastometry6.84 fold*h
Placebo Plus PlaceboMaximum Lysis in Thromboelastometry6.85 fold*h
p-value: 0.938Wilcoxon (Mann-Whitney)
Secondary

Plasmin-Antiplasmin Complexes

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.

Population: 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

ArmMeasureValue (MEDIAN)
LPS Plus DefibrotidePlasmin-Antiplasmin Complexes11.8 fold*h
LPS Plus PlaceboPlasmin-Antiplasmin Complexes9.99 fold*h
Placebo Plus DefibrotidePlasmin-Antiplasmin Complexes7 fold*h
Placebo Plus PlaceboPlasmin-Antiplasmin Complexes7.12 fold*h
p-value: 0.039Wilcoxon (Mann-Whitney)
Secondary

Plasminogen Activator Inhibitor 1

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.

Population: 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

ArmMeasureValue (MEDIAN)
LPS Plus DefibrotidePlasminogen Activator Inhibitor 1216 fold*h
LPS Plus PlaceboPlasminogen Activator Inhibitor 1477 fold*h
Placebo Plus DefibrotidePlasminogen Activator Inhibitor 125 fold*h
Placebo Plus PlaceboPlasminogen Activator Inhibitor 124.86 fold*h
p-value: 0.918Wilcoxon (Mann-Whitney)
Secondary

Thrombin-Antithrombin Complexes

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.

Population: 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

ArmMeasureValue (MEDIAN)
LPS Plus DefibrotideThrombin-Antithrombin Complexes23.39 fold*h
LPS Plus PlaceboThrombin-Antithrombin Complexes27.4 fold*h
Placebo Plus DefibrotideThrombin-Antithrombin Complexes17.46 fold*h
Placebo Plus PlaceboThrombin-Antithrombin Complexes21.83 fold*h
p-value: 0.148Wilcoxon (Mann-Whitney)
Secondary

Tissue-type Plasminogen Activator

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.

Population: 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

ArmMeasureValue (MEDIAN)
LPS Plus DefibrotideTissue-type Plasminogen Activator21.8 fold*h
LPS Plus PlaceboTissue-type Plasminogen Activator17 fold*h
Placebo Plus DefibrotideTissue-type Plasminogen Activator20.57 fold*h
Placebo Plus PlaceboTissue-type Plasminogen Activator23.54 fold*h
p-value: 0.026Wilcoxon (Mann-Whitney)
Secondary

Tumor Necrosis Factor (TNF)-Alpha

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.

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

ArmMeasureValue (MEDIAN)
LPS Plus DefibrotideTumor Necrosis Factor (TNF)-Alpha286 fold*h
LPS Plus PlaceboTumor Necrosis Factor (TNF)-Alpha326 fold*h
Placebo Plus DefibrotideTumor Necrosis Factor (TNF)-Alpha28.08 fold*h
Placebo Plus PlaceboTumor Necrosis Factor (TNF)-Alpha21.01 fold*h
p-value: 0.642Wilcoxon (Mann-Whitney)
Secondary

Von Willebrand Factor Antigen

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.

Population: 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.

ArmMeasureValue (MEDIAN)
LPS Plus DefibrotideVon Willebrand Factor Antigen54 %*h
LPS Plus PlaceboVon Willebrand Factor Antigen53 %*h
Placebo Plus DefibrotideVon Willebrand Factor Antigen27 %*h
Placebo Plus PlaceboVon Willebrand Factor Antigen26 %*h
p-value: 0.877Wilcoxon (Mann-Whitney)

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026