Severe Hepatic Veno-Occlusive DiseasePhase 3NCT00358501

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

A Phase 3 study testing Defibrotide in people with Severe Hepatic Veno-Occlusive Disease, run by Jazz Pharmaceuticals at 25 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

Search all trials

Trial 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. Read more about this study

Who is it for?: Any age
Conditions the study is for: Severe Hepatic Veno-Occlusive Disease
What is being tested?: Defibrotide
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 134 participants
Where: 25 sitesin 2 countries
Study dates: Jul 2006to Mar 2015
Phase: Phase 3
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 Any age
All sexes
No healthy volunteers
Child, Adult, Older adult

Who may be able to join

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.

Who cannot join

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

Trial locations and contacts

25 sites in 2 countries.

Country

City, postcode or hospital

25 sites in 2 countries

United States22 sites

Study site
Ann Arbor, Michigan
Study site
Atlanta, Georgia
Study site
Baltimore, Maryland
Study site
Boston, Massachusetts
Study site
Chicago, Illinois
Study site
Columbus, Ohio
Study site
Denver, Colorado
Study site
Duarte, California
Study site
Durham, North Carolina
Study site
Hackensack, New Jersey
Study site
Houston, Texas
Study site
Indianapolis, Indiana
Study site
Maywood, Illinois
Study site
Minneapolis, Minnesota
Study site
New York, New York
Study site
Omaha, Nebraska
Study site
Palo Alto, California
Study site
Philadelphia, Pennsylvania
Study site
Portland, Oregon
Study site
Rochester, Minnesota
Study site
Seattle, Washington
Study site
St Louis, Missouri

Other trials in United States

Canada3 sites

Study site
Montreal, Quebec
Study site
Toronto, Ontario
Study site
Vancouver, British Columbia

Other trials in Canada

About this study

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

Read the 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.

Conditions: Severe Hepatic Veno-Occlusive Disease
Being tested: Defibrotide
Keywords: Defibrotide, Severe veno occlusive disease, Multi organ failure, Stem cell transplant, Liver, Regimen related toxicity, Day 100 survival
Medical subject headings: Hepatic Veno-Occlusive Disease, Multiple Organ Failure

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

DefibrotideDrug
Defibrotide 6.25 mg/kg i.v. administered four times a day via 2 hour continuous infusion. Minimum duration 21 days.

Study groups in NCT00358501
Study group	Role	What they receive
Defibrotide	Experimental	Defibrotide treatment Receives: Drug: Defibrotide
Historical Control	No intervention	Historical control group

What is being measured

The primary outcome is the main question the study is designed to answer.

Survival at Day+100 Following Hematopoietic Stem Cell Transplant
The 95.1% CI instead of 95% CI is used for the final analysis to provide a small adjustment for the fact that an interim analysis was performed.
Measured: Day+100 post hematopoietic stem cell transplant
Complete Response by Day+100 Post Hematopoietic Stem Cell Transplant
The 95.1% CI instead of 95% CI is used for the final analysis to provide a small adjustment for the fact that an interim analysis was performed.
Measured: Day+100 post hematopoietic stem cell transplant

Secondary outcomes (2)

Survival at Day+180 Post Hematopoietic Stem Cell Transplantation
The 95.1% CI instead of 95% CI is used for the final analysis to provide a small adjustment for the fact that an interim analysis was performed.
Measured: 180 days post hematopoietic stem cell transplant
Percentage of Participants With Treatment-Emergent Adverse Events
Measured: Through 30 days from the last dose of Defibrotide

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Jul 2006Mar 2015

First posted1 Aug 2006 (estimated)
Study startJul 2006
Primary completionSep 2008
Study completionMar 2015

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.
Publications (3)Papers the sponsor has linked to this study.
Other trials for Severe Hepatic Veno-Occlusive DiseaseStudies of the same condition, open and under way.
More trials run by Jazz PharmaceuticalsThe sponsor's other registered studies.
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 3
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Single group
Masking: None (open label)
Enrolment: 134 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00358501
Sponsor's protocol ID: 2005-01
Status last verified: Dec 2016
First submitted: 28 Jul 2006
Last updated: 30 Jan 2017
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

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. doi: 10.1182/blood-2002-04-1216. Epub 2002 Aug 1.
PubMed 12393437
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).
Richardson PG, Riches ML, Kernan NA, Brochstein JA, Mineishi S, Termuhlen AM, Arai S, Grupp SA, Guinan EC, Martin PL, Steinbach G, Krishnan A, Nemecek ER, Giralt S, Rodriguez T, Duerst R, Doyle J, Antin JH, Smith A, Lehmann L, Champlin R, Gillio A, Bajwa R, D'Agostino RB Sr, Massaro J, Warren D, Miloslavsky M, Hume RL, Iacobelli M, Nejadnik B, Hannah AL, Soiffer RJ. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016 Mar 31;127(13):1656-65. doi: 10.1182/blood-2015-10-676924. Epub 2016 Jan 29.
PubMed 26825712

Study at a glance

From the registry record, last updated by the sponsor on 30 Jan 2017. Recruitment status is as the sponsor reported it: confirm with the study team.

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
ClinicalTrials.gov ID: NCT00358501
Acronym / sponsor ID: 2005-01
Conditions: Severe Hepatic Veno-Occlusive Disease
Keywords: Defibrotide, Severe veno occlusive disease, Multi organ failure, Stem cell transplant, Liver, Regimen related toxicity, Day 100 survival
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 134 participants (actual)
Lead sponsor: Jazz PharmaceuticalsIndustry (pharma, biotech, devices)
Collaborators: FDA Office of Orphan Products Development
Study start: Jul 2006
Primary completion: Sep 2008 (actual)
Study completion: Mar 2015 (actual)
First posted: 1 Aug 2006 (estimated)
Results: Posted 30 Jan 2017

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Single group
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
Defibrotide	Experimental	Drug: DefibrotideDefibrotide treatment
Historical Control	No intervention	–Historical control group

Who may qualify

Sex: All
Healthy volunteers: Not accepted
Age groups: Child, Adult, Older adult

Key inclusion criteria (3 listed)

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.

Key exclusion criteria (8 listed)

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

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
DefibrotideDefibrotide 6.25 mg/kg i.v. administered four times a day via 2 hour continuous infusion. Minimum duration 21 days.	Drug	Defibrotide

Primary outcome

Survival at Day+100 Following Hematopoietic Stem Cell Transplant
Time frame: Day+100 post hematopoietic stem cell transplant
The 95.1% CI instead of 95% CI is used for the final analysis to provide a small adjustment for the fact that an interim analysis was performed.
Complete Response by Day+100 Post Hematopoietic Stem Cell Transplant
Time frame: 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 secondary outcomes

Survival at Day+180 Post Hematopoietic Stem Cell Transplantation
Time frame: 180 days post hematopoietic stem cell transplant
Percentage of Participants With Treatment-Emergent Adverse Events
Time frame: Through 30 days from the last dose of Defibrotide

Results and safety

Results posted to the registry on 30 Jan 2017, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Defibrotide	102	102
Historical Control	32	32

Primary outcome: Survival at Day+100 Following Hematopoietic Stem Cell Transplant

Time frame: Day+100 post hematopoietic stem cell transplant. Number (95.1% Confidence Interval). Unit: percentage of participants

Measure	Defibrotide n = 102	Historical Control n = 32
Value	38.2 (28.8 to 47.7)	25.0 (9.9 to 40.1)

Population analysed: Intent-to-Treat

Primary outcome: Complete Response by Day+100 Post Hematopoietic Stem Cell Transplant

Time frame: Day+100 post hematopoietic stem cell transplant. Number (95.1% Confidence Interval). Unit: percentage of participants

Measure	Defibrotide n = 102	Historical Control n = 32
Value	25.5 (17.0 to 34.0)	12.5 (1.0 to 24.0)

Population analysed: Intent-to-Treat

2 secondary outcomes are reported in the full results.

Adverse events

Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Defibrotide	80 of 102 (78.4%)	91 of 102 (89.2%)	Not reported
Historical Control	0 of 0	0 of 0	Not reported

Limitations and caveats (from the sponsor): 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.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 30 Jan 2017.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 12393437Richardson 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. doi: 10.1182/blood-2002-04-1216. Epub 2002 Aug 1.
BackgroundRichardson, 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).
Derived from this study: PubMed 26825712Richardson PG, Riches ML, Kernan NA, Brochstein JA, Mineishi S, Termuhlen AM, Arai S, Grupp SA, Guinan EC, Martin PL, Steinbach G, Krishnan A, Nemecek ER, Giralt S, Rodriguez T, Duerst R, Doyle J, Antin JH, Smith A, Lehmann L, Champlin R, Gillio A, Bajwa R, D'Agostino RB Sr, Massaro J, Warren D, Miloslavsky M, Hume RL, Iacobelli M, Nejadnik B, Hannah AL, Soiffer RJ. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016 Mar 31;127(13):1656-65. doi: 10.1182/blood-2015-10-676924. Epub 2016 Jan 29.
Click here for more information about Defibrotide.Link provided by the sponsor.

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.

Paul Richardson, M.D. principal investigator

Dana-Farber Cancer Institute

25 sites in 2 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Defibrotide in people with Severe Hepatic Veno-Occlusive Disease, run by Jazz Pharmaceuticals at 25 sites in 2 countries.

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 3 inclusion and 8 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 30 Jan 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 25 sites in United States, Canada. 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. 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

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 30 Jan 2017). 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?

Survival at Day+100 Following Hematopoietic Stem Cell Transplant (time frame: Day+100 post hematopoietic stem cell transplant). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00358501, which also lists 3 linked publications.

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 30 Jan 2017.