A Phase 2 interventional study of Defibrotide in Thrombotic Microangiopathies, sponsored by University of California, San Francisco. Completed at 1 site in United States. Open to participants aged Up to 30 Years. Per ClinicalTrials.gov, last updated 2021-09-16.
Sponsored by University of California, San Francisco · Phase 2, Interventional, and Prevention
Thrombotic microangiopathy (TMA) is a common complication in the stem cell transplant population. Certain populations within the hematopoietic stem cell transplant (HSCT) population are at a higher risk than others. Defibrotide is an endothelial stabilizing agent which may prevent the endothelial damage that triggers TMA in HSCT patients. The feasibility, safety, and efficacy of defibrotide prophylaxis in a pediatric transplant population is unknown. Twenty five patients age 0 to 30 years receiving autologous or allogeneic hematopoeitic stem cell transplant who meet TMA high risk criteria will be enrolled. Patients will receive Defibrotide for 28-35 days starting before conditioning, and will be closely monitored for any adverse events up through 6 months post-transplant. The feasibility of administering defibrotide will be evaluated as well as incidence of TMA.
This is an open-label, single arm pilot study of defibrotide given as prophylaxis to patients receiving a conditioned stem cell transplant for the purpose of preventing post-transplant microangiopathy. The University of California San Francisco Blood and Marrow Transplant program reviewed all cases of non-relapse related death from 2012 through 2015 and identified a complication of endothelial injury known as transplant associated thrombotic microangiopathy (TMA) as the most common cause of transplant related mortality in its patient population. TMA is a multi-system disease in which widespread endothelial injury leads to microangiopathic hemolytic anemia, intravascular platelet activation and formation of thrombi within the microcirculation. Diagnosis of TMA can be difficult as systemic signs and symptoms of TMA are often similar to other common transplant complications, such as medication induced hypertension and cytopenias. The reported prevalence of TMA is varied likely due to diagnostic uncertainty and transplant center expertise, but large retrospective studies have reported it as 10-39%, with the majority of cases occurring in the first 100 days after transplant. Of the patients who develop TMA, approximately half of them will develop severe disease. Outcomes are poor with a reported 30-50% mortality rate and as high as 80% in patients with severe disease. Furthermore, survivors of TMA may have significant morbidity (e.g. renal failure and need for long-term dialysis, heart failure, and significantly prolonged hospital admission). There is no gold standard of treatment for TMA. Supportive care includes renal support, discontinuation of calcineurin inhibitors, and treatment of infections. Treatment options include plasma exchange, complement cascade blockade, and defibrotide. Early treatment is crucial to decrease morbidity and mortality.
Despite the early recognition and treatment of TMA, poor outcomes occur when patients are treated with complement blockade alone. This suggests that complement activation may trigger a complex cascade of parallel inflammatory mediators that lead to end organ damage independent of the complement pathway. The goal is to prevent TMA whenever possible via augmentation of endothelial repair. Defibrotide is an anticoagulant and fibrinolytic agent that has been shown to be an effective treatment in other endothelial disorders such as hepatic veno-occlusive disease. It is a polydeoxyribonucleotide salt that blocks plasminogen activator inhibitor-1 (PAI-1) and attenuates the effect of tumor necrosis factor. It also increases prostaglandin E2 and prostacyclin levels which alters the platelet activity adhesion and aggregation and relaxes the smooth muscle of blood vessel walls. All of this likely protects the endothelium from damage. It has been shown that patients with TMA who were treated with defibrotide had a 77% response rate.
The use of defibrotide in the context of veno occlusive disease (VOD) treatment and prevention has been studied extensively, including a landmark report showing that defibrotide given to children during stem cell transplant conditioning is safe and effective in the prevention of veno-occlusive disease. Also, defibrotide showed a 67-77% response rate when used as treatment in patients who developed TMA. However, there has not been a prospective study to show that such prophylaxis is effective in the prevention of TMA in pediatric patients undergoing hematopoetic stem cell transplant (HCT).
Patients will receive Defibrotide 6.25mg/kg via two hour intravenous infusions given every 6 hours. Defibrotide will start the day before conditioning is initiated, and will last for 28 to 35 days. During defibrotide administration, participants will have assessments of administration feasibility, hypersensitivity reaction, and bleeding. All hematopoietic stem cell transplant standard of care evaluations will be conducted, including routine clinical evaluations and laboratory assessments.
Patients will be followed for 6 months post-HSCT, or until death, whichever occurs first. All patients will be evaluated for toxicity from the time of their first treatment with the study drug. The study will use the CTCAE v4.03 for reporting of non-hematologic adverse events and modified criteria for hematologic adverse events. Patients removed from study for unacceptable treatment related adverse event(s) will be followed until resolution or stabilization of all treatment-related adverse events to Grade 2 or lower.
Biomarkers indicative of endothelial damage and TMA activity will be drawn to assess subclinical TMA activity as well as risk for subsequent development of TMA while on defibrotide. These include plasma free hemoglobin, suppression of tumorigenicity, angiopoietin 2, and plasminogen activator inhibitor - 1. Study labs will be assessed at 4 time points prior to Day +21, and at diagnosis of TMA.
52 studies on the registry are indexed under Thrombotic Microangiopathies; 21 are open to participants now.
This study's enrollment of 25 is below the median of 40 across 24 interventional studies indexed under Thrombotic Microangiopathies.
Browse Thrombotic Microangiopathies studies →University of California, San Francisco is the lead sponsor of 2,169 studies on the registry; 372 are open to participants now.
Of its 267 completed or terminated interventional studies of FDA-regulated products, 202 (76%) have results posted.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
5A. Patients undergoing tandem autologous transplant with thiotepa in one or more of the conditioning regimens
OR:
5B. . Patients with at least 3 of the following characteristics:
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The study doctor’s estimate of how long someone is likely to live. Criteria use it so that people can stay in the study long enough for it to answer its question.
A scale of how much an illness limits everyday activity. For people being assessed to join a study, scores run from 0 (fully active) to 4; lower is more active.
Studies most often ask for 0–1 or 0–2. Your doctor gives the score; the WHO scale uses the same steps. The full scale also has 5, which records death.
A 0–100 scale of how well someone can carry out everyday activities. 100 is no complaints and no signs of illness; 70 is able to look after yourself but not to work or keep up normal activity; 50 is needing considerable help and frequent medical care.
Studies often ask for 60 or 70 and above. Your doctor gives the score.
Stem cell (bone marrow) transplants. Allogeneic uses cells from a donor; autologous uses your own cells, collected earlier and given back.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Life expectancy
The study doctor’s estimate of how long someone is likely to live. Criteria use it so that people can stay in the study long enough for it to answer its question.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ECOG performance status
A scale of how much an illness limits everyday activity. For people being assessed to join a study, scores run from 0 (fully active) to 4; lower is more active.
Studies most often ask for 0–1 or 0–2. Your doctor gives the score; the WHO scale uses the same steps. The full scale also has 5, which records death.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Karnofsky performance status (KPS)
A 0–100 scale of how well someone can carry out everyday activities. 100 is no complaints and no signs of illness; 70 is able to look after yourself but not to work or keep up normal activity; 50 is needing considerable help and frequent medical care.
Studies often ask for 60 or 70 and above. Your doctor gives the score.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Allogeneic and autologous transplant
Stem cell (bone marrow) transplants. Allogeneic uses cells from a donor; autologous uses your own cells, collected earlier and given back.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
6.25mg/kg administered intravenously every 6 hours for 28 to 35 days, starting on the day before conditioning is initiated.
Drug: Defibrotide
Defibrotide is an anticoagulant and fibrinolytic agent that has been shown to be an effective treatment in other endothelial disorders such as hepatic veno-occlusive disease.
Also known as: Defitelio
Percent of Total Doses of Defibrotide That Were Missed [Feasibility]
Feasibility will be determined with regard to administration concurrently with chemotherapy and supportive medications before, during, and after stem cell infusion.
Time frame: From first treatment with study drug to day +21 post Transplant
Participants With Reportable Serious Adverse Events [Safety] Per CTACAE v5 Grade 3 or Higher
Safety was assessed by evaluating drug-related Serious Adverse Events per CTACAE v5 that occur after prophylactic administration of defibrotide. Analyses will be performed for all patients having received at least one dose of study drug.
Time frame: From first treatment with study drug to 6 months post-transplant
Participants With Clinically Significant Bleeding Requiring Discontinuation of Therapy [Safety]
Bleeding was assessed using Common Toxicity Criteria for Adverse Events version 4.03. (CTCAE). Study drug was permanently discontinued at grade 3 bleeding or higher. Analyses will be performed for all patients having received at least one dose of study drug.
Time frame: From first treatment with study drug to 6 months post-transplant
Participants With Hypersensitivity Reaction Requiring Discontinuation of Therapy [Safety]
Hypersensitivity reaction will be assessed using Common Toxicity Criteria for Adverse Events version 4.03. For grade 2 hypersensitivity reaction, study drug will be held until it resolves to grade 1 or lower. Study drug will be permanently discontinued at grade 3 hypersensitivity reaction or higher. Analyses will be performed for all patients having received at least one dose of study drug.
Time frame: From first treatment with study drug to 6 months post-transplant
Number of Patients With TMA Enrolled on the Study
Evidence of microangiopathy, with either clinical markers/organ dysfunction or presence of biomarkers, or one of the following: 1) presence of schistocytes in peripheral blood; 2) Histologic evidence of microangiopathy on a tissue specimen; 3) Undetectable haptoglobin with increased reticulocyte counts. If there is no evidence of microangiopathy but at least one clinical marker or at least 3 biomarkers, the participant will meet the criteria for TMA incidence. Based on prior analysis at our center, we anticipated an incidence of TA-TMA of 28.2% (95 CI, 17.8-38.6%) in the high-risk patients undergoing allogeneic transplants and 40% (95% CI, 13.9-69.5%) in the neuroblastoma patients undergoing planned tandem HSCT
Time frame: 6 months post-transplant
Number of Patients With Severe TMA
Severe TMA is defined as any TMA meeting the criteria in Objective 2 with the following complications: renal dysfunction requiring dialysis, pleural or pericardial effusion requiring any medical or surgical intervention, central nervous system dysfunction including seizure or posterior reversible encephalopathy syndrome, or death.
Time frame: 6 months post-transplant
Incidence of Elevation of Single or Combination of Biomarkers Predictive of Development of TMA
Values will be analyzed to determine whether any one biomarker or a combination of biomarkers may be predictive of TMA development or severity.
Time frame: 6 months post-transplant
Incidence of TMA
Evidence of microangiopathy, with either clinical markers/organ dysfunction or presence of biomarkers, or one of the following: 1) presence of schistocytes in peripheral blood; 2) Histologic evidence of microangiopathy on a tissue specimen; 3) Undetectable haptoglobin with increased reticulocyte counts. If there is no evidence of microangiopathy but at least one clinical marker or at least 3 biomarkers, the participant will meet the criteria for TMA incidence.
Time frame: Day 30, day 100 and day 180 post-transplant
Non Relapse Mortality
Deaths which cannot be attributed to disease relapse or progression
Time frame: Day 100 and day 180 post-transplant
| Milestone | Prophylactic Defibrotide |
|---|---|
| Started | 25 |
| Completed | 22 |
| Not completed | 3 |
| Withdrew: Adverse event | 3 |
Feasibility will be determined with regard to administration concurrently with chemotherapy and supportive medications before, during, and after stem cell infusion.
| percentage of missed doses | Prophylactic Defibrotide |
|---|---|
| Percent of Total Doses of Defibrotide That Were Missed [Feasibility] | 0.7 (0.5 to 2.0) |
Safety was assessed by evaluating drug-related Serious Adverse Events per CTACAE v5 that occur after prophylactic administration of defibrotide. Analyses will be performed for all patients having received at least one dose of study drug.
| Participants | Prophylactic Defibrotide |
|---|---|
| Participants With Reportable Serious Adverse Events [Safety] Per CTACAE v5 Grade 3 or Higher | 3 |
Bleeding was assessed using Common Toxicity Criteria for Adverse Events version 4.03. (CTCAE). Study drug was permanently discontinued at grade 3 bleeding or higher. Analyses will be performed for all patients having received at least one dose of study drug.
| Participants | Prophylactic Defibrotide |
|---|---|
| Participants With Clinically Significant Bleeding Requiring Discontinuation of Therapy [Safety] | 3 |
Hypersensitivity reaction will be assessed using Common Toxicity Criteria for Adverse Events version 4.03. For grade 2 hypersensitivity reaction, study drug will be held until it resolves to grade 1 or lower. Study drug will be permanently discontinued at grade 3 hypersensitivity reaction or higher. Analyses will be performed for all patients having received at least one dose of study drug.
| Participants | Prophylactic Defibrotide |
|---|---|
| Participants With Hypersensitivity Reaction Requiring Discontinuation of Therapy [Safety] | 3 |
Evidence of microangiopathy, with either clinical markers/organ dysfunction or presence of biomarkers, or one of the following: 1) presence of schistocytes in peripheral blood; 2) Histologic evidence of microangiopathy on a tissue specimen; 3) Undetectable haptoglobin with increased reticulocyte counts. If there is no evidence of microangiopathy but at least one clinical marker or at least 3 biomarkers, the participant will meet the criteria for TMA incidence. Based on prior analysis at our center, we anticipated an incidence of TA-TMA of 28.2% (95 CI, 17.8-38.6%) in the high-risk patients undergoing allogeneic transplants and 40% (95% CI, 13.9-69.5%) in the neuroblastoma patients undergoing planned tandem HSCT
| Participants | Prophylactic Defibrotide |
|---|---|
| Number of Patients With TMA Enrolled on the Study | 1 |
Severe TMA is defined as any TMA meeting the criteria in Objective 2 with the following complications: renal dysfunction requiring dialysis, pleural or pericardial effusion requiring any medical or surgical intervention, central nervous system dysfunction including seizure or posterior reversible encephalopathy syndrome, or death.
| Participants | Prophylactic Defibrotide |
|---|---|
| Number of Patients With Severe TMA | 0 |
Values will be analyzed to determine whether any one biomarker or a combination of biomarkers may be predictive of TMA development or severity.
Results for this outcome have not been posted.
Evidence of microangiopathy, with either clinical markers/organ dysfunction or presence of biomarkers, or one of the following: 1) presence of schistocytes in peripheral blood; 2) Histologic evidence of microangiopathy on a tissue specimen; 3) Undetectable haptoglobin with increased reticulocyte counts. If there is no evidence of microangiopathy but at least one clinical marker or at least 3 biomarkers, the participant will meet the criteria for TMA incidence.
| Participants | Prophylactic Defibrotide |
|---|---|
| Day 30 | 1 |
| day 100 | 0 |
| Day 180 | 0 |
Deaths which cannot be attributed to disease relapse or progression
Results for this outcome have not been posted.
Collected over 6 months. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Prophylactic Defibrotide | 0/25 (0%) | 3/25 (12%) | 0/25 (0%) |
| Event | Prophylactic Defibrotide |
|---|---|
| BleedingGeneral disorders | 3/25 |
25 patients who started therapy
| Age, Categorical(Participants) | Prophylactic Defibrotide |
|---|---|
| <=18 years | 22 |
| Between 18 and 65 years | 3 |
| >=65 years | 0 |
| Sex: Female, Male(Participants) | Prophylactic Defibrotide |
|---|---|
| Female | 10 |
| Male | 15 |
| Race (NIH/OMB)(Participants) | Prophylactic Defibrotide |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 7 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 1 |
| White | 15 |
| More than one race | 2 |
| Unknown or Not Reported | 0 |
| Diagnosis(Participants) | Prophylactic Defibrotide |
|---|---|
| Leukemia | 9 |
| Lymphoma | 2 |
| Neuroblastoma | 14 |
| Recipient CMV (cytomegalovirus) serostatus(Participants) | Prophylactic Defibrotide |
|---|---|
| Positive | 14 |
| Negative | 11 |
| Donor type(Participants) | Prophylactic Defibrotide |
|---|---|
| Unrelated | 1 |
| Haploidentical | 10 |
| N/A (Autologous) | 14 |
| MIBG (Metaiodobenzylguanidine) therapy prior to transplant(Participants) | Prophylactic Defibrotide |
|---|---|
| Yes | 4 |
| No | 21 |
| Conditioning backbone(Participants) | Prophylactic Defibrotide |
|---|---|
| TBI based | 3 |
| Melphalan based | 6 |
| Busulfan based | 2 |
| Other (Autologous) | 14 |
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: Yes — Individual participant data that underlie the results reported in scientific journals after de-identification.
Supporting information: Study protocol
Time frame: Beginning 3 months and ending 5 years following article publication
Access criteria: Researchers can submit a request for access to the study Steering Committee. If the proposal is determined to be methodologically sound, data requestors will need to sign a data access agreement prior to gaining access.
Ran from May 2018 to primary completion in Jul 2020, 26 months.
Results were first posted in Sep 2021, 1 year 1 month after primary completion.
How these figures are worked out, and which studies are left out of them.
This study is completed, as verified in Sep 2021. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Studies of the drug tested here: Defibrotide
Thrombotic Microangiopathies →
University of California, San Francisco →