Veno-occlusive DiseasePhase 2NCT00003966
Defibrotide in Treating Patients With Liver Damage Following Peripheral Stem Cell Transplantation
A Phase 2 study testing defibrotide in people with Veno-occlusive Disease, run by Dana-Farber Cancer Institute at 9 sites in United States.
Trial summary
RATIONALE: Giving defibrotide may be an effective treatment for liver damage that may result following peripheral stem cell transplantation. PURPOSE: This randomized phase II trial is studying defibrotide to see how well it works in treating patients with severe liver disease after undergoing peripheral stem cell… Read more about this study
- Who is it for?
- Ages Up to 18 years
- Conditions the study is for
- 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
- 151 participants
- Where
- 9 sitesUnited States
- Study dates
- Apr 2000to Apr 2006
- Phase
- Phase 2
- Are there results?
- None posted in the registry
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 Up to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Clinical diagnosis of VOD defined by:
- Jaundice (bilirubin ≥ 2 mg/dL) and 2 or more of the following: ascites, weight gain > 5% above baseline weight (see Section 5.2), hepatomegaly, RUQ pain
- Patients with jaundice and reversal of flow on Doppler examination of the portal vein will be eligible with one of the following: ascites, weight gain > 5% above baseline weight, hepatomegaly, RUQ pain
- Patients with pre-existing hepatomegaly must have documentation by physical exam or imaging that liver size is increased over baseline at admission
- Patients who do not meet the criteria in Section 3.1.1 (ie. have two of the major criteria but not three) and have biopsy proven VOD are eligible in the presence of characteristics consistent with severe disease (see below).
- Patients with concurrent, confounding causes of liver dysfunction clinically evident or evident on ultrasound or other radiographic imaging (such as evidence of biliary ductal dilatation or focal tissue defects) may require biopsy-proven VOD and/or elevated wedged trans-hepatic venous pressure gradient measurement ( ≥10 mm mercury) to be considered eligible. Best medical judgment and further imaging studies can be used to clarify the diagnosis and determine confounding causes of liver dysfunction.
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- Severity of VOD defined by:
- For patients addressed by the Bearman model (i.e. within 16 days of SCT and conditioned with either BU/CY, CY/TBI or CBV), there must be a 30% or greater risk of severe VOD (see Appendix B).
- For all other patients who are not addressed by the Bearman model (ie. beyond 16 days of SCT and/or not conditioned with either BU/CY,
- CY/TBI or CBV), there must be concomitant multi-organ failure defined as presence of one or more of the following :
- renal dysfunction: a) creatinine ≥2x value on the date of admission day to the BMT unit for conditioning or ≥2x lowest value during conditioning (use the lowest value for calculation), or b) creatinine clearance or GFR ≤50% of admission value, or c) dialysis dependence"
- pulmonary dysfunction: documentation of oxygenation saturation ≤ 90% on room air; requirement for positive pressure/ventilator dependence
- ----pulmonary dysfunction must not be attributable to another cause (e.g. documented infectious pneumonia)
- central nervous dysfunction: documentation of confusion, lethargy, and/or delirium ---- central nervous dysfunction must not be attributable to another cause (e.g. documented cyclosporin toxicity)
- Patients or their parents/guardians or designated proxy must have the ability to give voluntary informed consent to the protocol. Where possible, patient assent will also be obtained
- Patients must be ≥ 12 hours after cessation of heparin
- Patient must have an eligible diagnosis of VOD by Day 35 post transplant
Who cannot join
- Patients receiving concomitant heparin or other anticoagulants unless being used for routine CVL management, fibrinolytic instillation for CVL occlusion, intermittent dialysis or ultrafiltration are excluded. Patients who have received systemic t-PA (concomitant or prior) are excluded.
- Patients with significant uncontrolled acute bleeding, defined as hemorrhage requiring > 15 cc/kg of packed red blood cells (ie. a pediatric patient weighing 20 kg and requiring > 300cc of packed red blood cells /24 hours or an adult patient weighing 70 kg and requiring >3 units of packed red blood cells/24 hours) to replace blood loss are excluded. These parameters must be reviewed prior to enrollment by the PI or his/her designate.
- Patients with hemodynamic instability as defined below:
- Hemodynamic stability is defined as having no requirement for pressor support OR being able to maintain mean arterial pressure within 1 SD of age-adjusted levels with pressor support (see Appendix D)
- Patients requiring renal dose dopamine alone (2-5 mcg/kg/min) are eligible without measurement of mean arterial pressure
- Patients with Grade B-D GVHD, graded according to the IBMTR Severity Index (see Appendix G). Please note patients with Grade B skin only are eligible.
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- Patients intubated for documented intrinsic lung disease
- --- Patients intubated secondary to a mechanical barrier to ventilation, e.g.pulmonary edema or ascites, will be eligible as long as the PaO2/FiO2 ratio is ≥ 300 and/or the oxygen index (OI={MAP x FiO2}÷ PaO2 x 100) is ≤ 25% at the time of enrollment
- Patients who meet Grade IV common toxicity criteria for neurotoxicity (other than Grade IV confusion and/or delirium), i.e. coma, seizures, toxic psychosis
- Patients who are currently receiving treatment with another experimental agent.
- Please note that an experimental agent in this setting is defined as any drug or device used under an IND designation which is associated with systemic effects that could influence the outcome in a patient with severe VOD. If the continued use of an experimental agent is considered both necessary and appropriate, this must be reviewed and approved on a case by case basis by the Overall Study PI, Dr. Paul Richardson, or his designate, who will approve the entry of patients being concurrently treated with another experimental agent only if there is no evidence for a potential adverse pharmacokinetic interaction or overlapping toxicity.
Trial locations and contacts
9 sites in 1 country.
9 sites in 1 country
United States9 sites
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, 21231-2410
Children's Hospital Boston
Boston, Massachusetts, 02115
Dana Farber Cancer Institute
Boston, Massachusetts, 02115
Massachusetts General Hospital
Boston, Massachusetts, 02115
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
City of Hope Comprehensive Cancer Center
Duarte, California, 91010-3000
Duke Comprehensive Cancer Center
Durham, North Carolina, 27710
Memorial Sloan-Kettering Cancer Center
New York, New York, 10021
Fred Hutchinson Cancer Research Center
Seattle, Washington, 98109-1024
About this study
Official title: Defibrotide for Hematopoietic Stem Cell Transplant Patients With Severe Hepatic Venocclusive Disease: A Phase I/II Study to Determine the Minimal Effective Dose
RATIONALE: Giving defibrotide may be an effective treatment for liver damage that may result following peripheral stem cell transplantation.
PURPOSE: This randomized phase II trial is studying defibrotide to see how well it works in treating patients with severe liver disease after undergoing peripheral stem cell transplantation.
Read the detailed description
OBJECTIVES:
- Determine complete response rate in post-hematopoietic stem cell transplant patients with severe veno-occlusive disease of the liver treated with defibrotide.
- Determine the minimal effective dose of this drug in these patients.
- Assess toxicity and adverse side effects of this drug in these patients.
OUTLINE: This is a randomized, multicenter study. All patients initially receive the same dose of defibrotide IV over 2 hours every 6 hours on day 1. On day 2, patients are randomized to 1 of 2 doses of defibrotide.
- Arm I: On days 2-14, patients receive a lower dose of defibrotide IV over 2 hours every 6 hours.
- Arm II: On days 2-14, patients receive a higher dose of defibrotide IV over 2 hours every 6 hours.
In both arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
PROJECTED ACCRUAL: A total of 140 patients (70 per treatment arm) will be accrued for this study.
- Conditions
- Veno-occlusive Disease
- Being tested
- defibrotide
- Keywords
- veno-occlusive disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
defibrotideDrug
Also called Defitelio®
| Study group | Role | What they receive |
|---|---|---|
| Arm A Lower dose | Experimental | This is a randomized, multicenter study. All patients initially receive the same dose of defibrotide IV over 2 hours every 6 hours on day 1. On day 2, patients are randomized to 1 of 2 doses of defibrotide.
- Arm I: On days 2-14, patients receive a lower dose of defibrotide IV over 2 hours every 6 hours.
In both arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity Receives: Drug: defibrotide |
| Arm B Higher Dose | Experimental | This is a randomized, multicenter study. All patients initially receive the same dose of defibrotide IV over 2 hours every 6 hours on day 1. On day 2, patients are randomized to 1 of 2 doses of defibrotide.
- Arm II: On days 2-14, patients receive a higher dose of defibrotide IV over 2 hours every 6 hours.
In both arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity Receives: Drug: defibrotide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Complete Response Rate as measured by a total bilirubin of < 2 mg/dL and resolution of multi-organ failure attributable to veno-occlusive disease (VOD)
Measured: 60 Days
Secondary outcomes (6)
Survival at 100 days following stem cell transplantation
Measured: 100 days following stem cell transplantation
Toxicity by NCI Common Toxicity Criteria version 2.0 during study and 30 days after study completion
Measured: during study and 30 Days after study completion
Grade 3-4 end organ dysfunction attributable to defibrotide as determined by NCI Common Toxicity Criteria version 2.0 during study and 30 days after study completion
Measured: during study and 30 Days after study completion
Occurrence of other adverse events by NCI Common Toxicity Criteria version 2.0 during study and 30 days after study completion
Measured: during study and 30 Days after study completion
Effect of drug on plasminogen activator inhibitor-1 (PAI-1) determination of dose-relationship between drug and/or VOD response as measured by survival, PAI-1 levels, and research assays at day 100
Measured: 100 Days
Feasibility of pharmacokinetics (PK) across dose arms and the PK of defibrotide by PK analysis
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jan 2003 (estimated)
- Study startApr 2000
- Primary completionFeb 2006
- Study completionApr 2006
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Veno-occlusive DiseaseStudies of the same condition, open and under way.
- More trials run by Dana-Farber Cancer InstituteThe 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 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 151 participants (actual)
Sponsor and investigators
- Lead sponsor
- Dana-Farber Cancer Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Jazz Pharmaceuticals, National Cancer Institute (NCI)
- Responsible party
- Principal investigator, Paul G. Richardson, MD, Dana-Farber Cancer Institute
- Investigators
- Paul Richardson, MD, Principal investigator, Dana-Farber Cancer Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00003966
- Sponsor's protocol ID
- 99118
- Other IDs
- P30CA015704, DFCI-1999-P-010076/14, DUMC-00176-00-2, FHCRC-1375.00, NCI-G99-1548, CHNMC-02118, MSKCC-03-058, JHMI-00-06-02-02
- Status last verified
- Jan 2017
- First submitted
- 1 Nov 1999
- Last updated
- 20 Jan 2017
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
Richardson PG, Soiffer RJ, Antin JH, et 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 104 (11): A-350, 2004.
Richardson P, Soiffer RJ, Antin JH, et al.: Defibrotide (DF) is effective in the treatment of severe veno-occlusive disease (VOD) and multi-system organ failure (MOF) post stem cell transplantation (SCT): results of a phase II, multicenter, randomized study. [Abstract] Blood 102 (11): A-674, 2003.
Richardson PG, Soiffer R, Antin JH, et al.: Defibrotide (DF) appears effective and safe in a phase II, randomized study of patients (pts) with severe veno-occlusive disease (VOD) and multi-system organ failure (MOF) post stem cell transplantation (SCT). [Abstract] Blood 100 (9): A-414, 2002.
Study at a glance
From the registry record, last updated by the sponsor on 20 Jan 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Defibrotide for Hematopoietic Stem Cell Transplant Patients With Severe Hepatic Venocclusive Disease: A Phase I/II Study to Determine the Minimal Effective Dose
- ClinicalTrials.gov ID
- NCT00003966
- Acronym / sponsor ID
- 99118
- Conditions
- Veno-occlusive Disease
- Keywords
- veno-occlusive disease
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 151 participants (actual)
- Lead sponsor
- Dana-Farber Cancer InstituteUniversity, hospital or other
- Collaborators
- Jazz Pharmaceuticals, National Cancer Institute (NCI)
- Study start
- Apr 2000
- Primary completion
- Feb 2006 (actual)
- Study completion
- Apr 2006 (actual)
- First posted
- 27 Jan 2003 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
RATIONALE: Giving defibrotide may be an effective treatment for liver damage that may result following peripheral stem cell transplantation.
PURPOSE: This randomized phase II trial is studying defibrotide to see how well it works in treating patients with severe liver disease after undergoing peripheral stem cell transplantation.
Detailed description
OBJECTIVES:
- Determine complete response rate in post-hematopoietic stem cell transplant patients with severe veno-occlusive disease of the liver treated with defibrotide.
- Determine the minimal effective dose of this drug in these patients.
- Assess toxicity and adverse side effects of this drug in these patients.
OUTLINE: This is a randomized, multicenter study. All patients initially receive the same dose of defibrotide IV over 2 hours every 6 hours on day 1. On day 2, patients are randomized to 1 of 2 doses of defibrotide.
- Arm I: On days 2-14, patients receive a lower dose of defibrotide IV over 2 hours every 6 hours.
- Arm II: On days 2-14, patients receive a higher dose of defibrotide IV over 2 hours every 6 hours.
In both arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
PROJECTED ACCRUAL: A total of 140 patients (70 per treatment arm) will be accrued for this study.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm A Lower dose | Experimental | Drug: defibrotideThis is a randomized, multicenter study. All patients initially receive the same dose of defibrotide IV over 2 hours every 6 hours on day 1. On day 2, patients are randomized to 1 of 2 doses of defibrotide. - Arm I: On days 2-14, patients receive a lower dose of defibrotide IV over 2 hours every 6 hours. In both arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity |
| Arm B Higher Dose | Experimental | Drug: defibrotideThis is a randomized, multicenter study. All patients initially receive the same dose of defibrotide IV over 2 hours every 6 hours on day 1. On day 2, patients are randomized to 1 of 2 doses of defibrotide. - Arm II: On days 2-14, patients receive a higher dose of defibrotide IV over 2 hours every 6 hours. In both arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity |
Who may qualify
- Ages
- Up to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (17 listed)
- Clinical diagnosis of VOD defined by:
- Severity of VOD defined by:
- ----pulmonary dysfunction must not be attributable to another cause (e.g. documented infectious pneumonia)
Key exclusion criteria (11 listed)
- --- Patients intubated secondary to a mechanical barrier to ventilation, e.g.pulmonary edema or ascites, will be eligible as long as the PaO2/FiO2 ratio is ≥ 300 and/or the oxygen index (OI={MAP x FiO2}÷ PaO2 x 100) is ≤ 25% at the time of enrollment
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 |
|---|---|---|
| defibrotideAlso: Defitelio® | Drug | Arm A Lower dose, Arm B Higher Dose |
Primary outcome
Complete Response Rate as measured by a total bilirubin of < 2 mg/dL and resolution of multi-organ failure attributable to veno-occlusive disease (VOD)
Time frame: 60 Days
6 secondary outcomes
Survival at 100 days following stem cell transplantation
Time frame: 100 days following stem cell transplantation
Toxicity by NCI Common Toxicity Criteria version 2.0 during study and 30 days after study completion
Time frame: during study and 30 Days after study completion
Grade 3-4 end organ dysfunction attributable to defibrotide as determined by NCI Common Toxicity Criteria version 2.0 during study and 30 days after study completion
Time frame: during study and 30 Days after study completion
Occurrence of other adverse events by NCI Common Toxicity Criteria version 2.0 during study and 30 days after study completion
Time frame: during study and 30 Days after study completion
Effect of drug on plasminogen activator inhibitor-1 (PAI-1) determination of dose-relationship between drug and/or VOD response as measured by survival, PAI-1 levels, and research assays at day 100
Time frame: 100 Days
Feasibility of pharmacokinetics (PK) across dose arms and the PK of defibrotide by PK analysis
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Jan 2017.
- Results publicationRichardson PG, Soiffer RJ, Antin JH, et 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 104 (11): A-350, 2004.
- Results publicationRichardson P, Soiffer RJ, Antin JH, et al.: Defibrotide (DF) is effective in the treatment of severe veno-occlusive disease (VOD) and multi-system organ failure (MOF) post stem cell transplantation (SCT): results of a phase II, multicenter, randomized study. [Abstract] Blood 102 (11): A-674, 2003.
- Results publicationRichardson PG, Soiffer R, Antin JH, et al.: Defibrotide (DF) appears effective and safe in a phase II, randomized study of patients (pts) with severe veno-occlusive disease (VOD) and multi-system organ failure (MOF) post stem cell transplantation (SCT). [Abstract] Blood 100 (9): A-414, 2002.
- Individual participant dataSharing planned: No
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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, MD principal investigator
Dana-Farber Cancer Institute
9 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing defibrotide in people with Veno-occlusive Disease, run by Dana-Farber Cancer Institute at 9 sites in United States.
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 17 inclusion and 11 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 20 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 9 sites in United States. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Complete Response Rate as measured by a total bilirubin of < 2 mg/dL and resolution of multi-organ failure attributable to veno-occlusive disease (VOD) (time frame: 60 Days). 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 NCT00003966, 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 20 Jan 2017.