NCT03384693

Defibrotide TMA Prophylaxis Pilot Trial

Completed Phase 2 Results posted Last updated 16 September 2021

What this trial tests

Phase 2 trial testing Defibrotide in Thrombotic Microangiopathies in 25 participants. Completed in 31 July 2020.

Timeline

1 May 2018

Primary endpoint
31 July 2020

31 July 2020

Quick facts

Lead sponsor	University of California, San Francisco
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	prevention
Enrollment	25
Start date	1 May 2018
Primary completion	31 July 2020
Estimated completion	31 July 2020
Sites	1 location across United States

Drugs / interventions tested

• Defibrotide (DEFIBROTIDE) — full drug profile →

Conditions studied

• Thrombotic Microangiopathies — all drugs for Thrombotic Microangiopathies →

Sponsor

University of California, San Francisco

Who can join

Under 30, any sex, with Thrombotic Microangiopathies. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percent of Total Doses of Defibrotide That Were Missed [Feasibility] Primary · From first treatment with study drug to day +21 post Transplant

Feasibility will be determined with regard to administration concurrently with chemotherapy and supportive medications before, during, and after stem cell infusion.

Group	Value	95% CI
Prophylactic Defibrotide	0.7	0.5 – 2.0

Participants With Reportable Serious Adverse Events [Safety] Per CTACAE v5 Grade 3 or Higher Primary · From first treatment with study drug to 6 months post-transplant

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.

Group	Value	95% CI
Prophylactic Defibrotide	3

Participants With Clinically Significant Bleeding Requiring Discontinuation of Therapy [Safety] Primary · From first treatment with study drug to 6 months post-transplant

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.

Group	Value	95% CI
Prophylactic Defibrotide	3

Participants With Hypersensitivity Reaction Requiring Discontinuation of Therapy [Safety] Primary · From first treatment with study drug to 6 months post-transplant

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.

Group	Value	95% CI
Prophylactic Defibrotide	3

Number of Patients With TMA Enrolled on the Study Secondary · 6 months post-transplant

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 un

Group	Value	95% CI
Prophylactic Defibrotide	1

Number of Patients With Severe TMA Secondary · 6 months post-transplant

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.

Group	Value	95% CI
Prophylactic Defibrotide	0

Incidence of TMA Secondary · Day 30, day 100 and day 180 post-transplant

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.

Day 30

Group	Value	95% CI
Prophylactic Defibrotide	1

day 100

Group	Value	95% CI
Prophylactic Defibrotide	0

Day 180

Group	Value	95% CI
Prophylactic Defibrotide	0

Adverse events — posted to ClinicalTrials.gov

Time frame: 6 months. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Prophylactic Defibrotide

Serious: 3/25 (12%)

Deaths: 0/25

Serious adverse events (1 terms)

Reaction	System	Prophylactic Defibrotide
Bleeding	General disorders	—

Most-reported serious reactions: Bleeding.

Data from ClinicalTrials.gov NCT03384693 adverse events section.

Sponsor's own description

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.

Publications & conference data

5 peer-reviewed publications reference this trial (live from Europe PMC):

1. COVID-19-induced endotheliitis: emerging evidence and possible therapeutic strategies.
   Calabretta E, Moraleda JM, Iacobelli M, Jara R, et al · · 2021 · cited 58× · PMID 33538335 · DOI 10.1111/bjh.17240
2. Endothelial Dysfunction after Hematopoietic Stem Cell Transplantation: A Review Based on Physiopathology.
   Milone G, Bellofiore C, Leotta S, Milone GA, et al · · 2022 · cited 42× · PMID 35160072 · DOI 10.3390/jcm11030623
3. Risk Factors for Transplant-Associated Thrombotic Microangiopathy after Autologous Hematopoietic Cell Transplant in High-Risk Neuroblastoma.
   Tolbert VP, Dvorak CC, Golden C, Vissa M, et al · · 2019 · cited 16× · PMID 31199983 · DOI 10.1016/j.bbmt.2019.06.006
4. Emerging therapeutic and preventive approaches to transplant-associated thrombotic microangiopathy.
   Schoettler M, Chonat S, Williams K, Lehmann L. · · 2021 · cited 9× · PMID 34534983 · DOI 10.1097/moh.0000000000000687
5. The Development of New Agents for Post-Hematopoietic Stem Cell Transplantation Non-Infectious Complications in Children.
   Ilan U, Brivio E, Algeri M, Balduzzi A, et al · · 2023 · cited 2× · PMID 36983151 · DOI 10.3390/jcm12062149