Healthy VolunteersPhase 4LPS_DFNCT02876601
Defibrotide in the Human Endotoxemia Model --- an Exploratory Trial Investigating the Effects and the Mechanisms of Defibrotide
A Phase 4 study testing Defibrotide and Lipopolysaccharide in people with Healthy Volunteers and Endotoxemia, run by Bernd Jilma at 1 site in Austria.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Healthy Volunteers, Endotoxemia
- What is being tested?
- Defibrotide and Lipopolysaccharide
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 20 participants
- Where
- 1 siteAustria
- Study dates
- 18 Apr 2017to 12 Feb 2018
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- >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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
Austria1 site
Department of Clinical Pharmacology, Medical University of Vienna
Vienna, 1090
About this study
Official title: Defibrotide in the Human Endotoxemia Model -- an Exploratory Trial Investigating the Effects and the Mechanisms of Defibrotide
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.
Read the 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.
- Conditions
- Healthy Volunteers, Endotoxemia
- Being tested
- Defibrotide, Placebo (0.9% sodium chloride), Lipopolysaccharide, Placebo (0.9% sodium chloride bolus)
- Keywords
- Coagulation, Inflammation, Defibrotide, Fibrinolysis
- Medical subject headings
- Endotoxemia, Thrombosis, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DefibrotideDrug
6.25mg/kg bodyweight over 2h infusion
Placebo (0.9% sodium chloride)Drug
(0.9% sodium chloride) infusion over 2h infusion
LipopolysaccharideDrug
bolus infusion of 2ng/kg bodyweight lps
Placebo (0.9% sodium chloride bolus)Drug
(0.9% sodium chloride) bolus infusion
| Study group | Role | What they receive |
|---|---|---|
| Defibrotide/LPS | Active comparator | 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 Receives: Drug: Defibrotide; Drug: Lipopolysaccharide |
| Placebo/LPS | Placebo comparator | 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 Receives: Drug: Placebo (0.9% sodium chloride); Drug: Lipopolysaccharide |
| Defibrotide/Placebo | Other | 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 Receives: Drug: Defibrotide; Drug: Placebo (0.9% sodium chloride bolus) |
| Placebo/Placebo | Other | 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 Receives: Drug: Placebo (0.9% sodium chloride); Drug: Placebo (0.9% sodium chloride bolus) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: The parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h.
Secondary outcomes (10)
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
Measured: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
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
Measured: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, and 6h and AUC was calculated based on these measurements.
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.
Measured: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
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.
Measured: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
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.
Measured: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
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.
Measured: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
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.
Measured: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
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.
Measured: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
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.
Measured: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
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.
Measured: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h and AUC was calculated based on these measurements.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Aug 2016 (estimated)
- Study start18 Apr 2017
- Primary completion12 Feb 2018
- Study completion12 Feb 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Healthy VolunteersStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- 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.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Bernd Jilma
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Bernd Jilma, Medical University of Vienna
- Investigators
- Bernd Jilma, MD, Principal investigator, Medical University of Vienna
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02876601
- Sponsor's protocol ID
- LPS_DF Version 1.4
- Acronym
- LPS_DF
- Status last verified
- Dec 2019
- First submitted
- 27 Jun 2016
- Last updated
- 19 Dec 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Data will be published in a peer-reviewed medical journal, individual data will not be presented or published, but may be made available by direct request to the PI (data may be made available in an anonymized fashion)
Study at a glance
From the registry record, last updated by the sponsor on 19 Dec 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Defibrotide in the Human Endotoxemia Model -- an Exploratory Trial Investigating the Effects and the Mechanisms of Defibrotide
- ClinicalTrials.gov ID
- NCT02876601
- Acronym / sponsor ID
- LPS_DF / LPS_DF Version 1.4
- Conditions
- Healthy Volunteers, Endotoxemia
- Keywords
- Coagulation, Inflammation, Defibrotide, Fibrinolysis
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Bernd JilmaUniversity, hospital or other
- Study start
- 18 Apr 2017 (actual)
- Primary completion
- 12 Feb 2018 (actual)
- Study completion
- 12 Feb 2018 (actual)
- First posted
- 24 Aug 2016 (estimated)
- Results
- Posted 19 Dec 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
- 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.
| Arm | Type | Receives |
|---|---|---|
| Defibrotide/LPS | Active comparator | Drug: Defibrotide, Drug: Lipopolysaccharide2ng/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 |
| Placebo/LPS | Placebo comparator | Drug: Placebo (0.9% sodium chloride), Drug: Lipopolysaccharide2ng/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 |
| Defibrotide/Placebo | Other | Drug: Defibrotide, Drug: Placebo (0.9% sodium chloride bolus)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 |
| Placebo/Placebo | Other | Drug: Placebo (0.9% sodium chloride), Drug: Placebo (0.9% sodium chloride bolus)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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- >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
Key exclusion criteria (7 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Defibrotide6.25mg/kg bodyweight over 2h infusion | Drug | Defibrotide/LPS, Defibrotide/Placebo |
| Placebo (0.9% sodium chloride)(0.9% sodium chloride) infusion over 2h infusion | Drug | Placebo/LPS, Placebo/Placebo |
| Lipopolysaccharidebolus infusion of 2ng/kg bodyweight lps | Drug | Defibrotide/LPS, Placebo/LPS |
| Placebo (0.9% sodium chloride bolus)(0.9% sodium chloride) bolus infusion | Drug | Defibrotide/Placebo, Placebo/Placebo |
Primary outcome
Prothrombin Fragments f1+2
Time frame: 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
10 secondary outcomes
Thrombin-Antithrombin Complexes
Time frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Plasmin-Antiplasmin Complexes
Time frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, and 6h and AUC was calculated based on these measurements.
Tumor Necrosis Factor (TNF)-Alpha
Time frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Tissue-type Plasminogen Activator
Time frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Interleukin-6
Time frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
E-Selectin
Time frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Plasminogen Activator Inhibitor 1
Time frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Von Willebrand Factor Antigen
Time frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Clotting Time in Thromboelastometry
Time frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h and AUC was calculated based on these measurements.
Maximum Lysis in Thromboelastometry
Time frame: This parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h and AUC was calculated based on these measurements.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Dec 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No. Data will be published in a peer-reviewed medical journal, individual data will not be presented or published, but may be made available by direct request to the PI (data may be made available in an anonymized fashion)
Related trials for Healthy Volunteers
Not yet recruiting
Neuroergonomic Analysis of a Brain-Computer Interface Device (BCI)
Healthy Volunteers - Male and Female
RecruitingPhase 1
First-in-Human Trial to Assess REGN20423 in Healthy Adult Participants and Adult Participants With Atopic Dermatitis
Healthy Volunteer, Atopic Dermatitis
Not yet recruitingObservational study
Establishment of Biobank of Nasal Epithelium Samples From Healthy Volunteers
Healthy
RecruitingObservational study
Improved Methods of Cell Selection for Bone Marrow Transplant Alternatives
Graft-Versus-Host Disease, Graft-versus-leukemia
Not yet recruitingObservational study
Screening Protocol
Pain
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bernd Jilma, MD principal investigator
Medical University of Vienna
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Defibrotide and Lipopolysaccharide in people with Healthy Volunteers and Endotoxemia, run by Bernd Jilma at 1 site in Austria.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Dec 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Austria. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 19 Dec 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Prothrombin Fragments f1+2 (time frame: The parameter was assessed at baseline, at 0h, 1h, 2h, 4h, 6h, 24h.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Dec 2019.