Jazz Pharmaceuticals Stops Enrollment in Phase 3 Study Evaluating Defibrotide for the Prevention of Veno-Occlusive Disease
The IDMC recommendation was made after completion of a pre-planned interim analysis of the first 280 patients and where the study met the protocol-specified futility criteria. The study was conducted as part of a post-marketing requirement related to safety. The IDMC conducted multiple periodic safety analyses during the study and reported no new safety concerns.
"We are disappointed with this outcome, but wish to thank the patients and physicians involved in the program for their participation in the study," said
Jazz has notified relevant health authorities and study investigators of the decision to discontinue new enrollment to the study. Patients enrolled in the study will be allowed to continue participation if they and the investigator determine this would be in the patient's best interest. Patients will continue to be followed per protocol. The full data will be submitted to a future medical meeting for presentation.
This Phase 3 trial was not designed to further evaluate defibrotide for the treatment of VOD and does not impact the approved indication or other ongoing clinical studies. Defitelio® (defibrotide sodium) remains the only treatment approved for the treatment of adult and pediatric patients with hepatic VOD, also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction following HSCT. Defibrotide is currently being investigated in two Phase 2 company-sponsored studies for the prevention of acute Graft-versus-Host-Disease and the prevention of neurotoxicity in patients with relapsed or refractory diffuse large B-cell lymphoma receiving CAR T-cell therapy.
About the Phase 3 Clinical Program
The Phase 3 study was a randomized, open-label, multi-center trial with an adaptive design comparing the efficacy of defibrotide versus best supportive care in the prevention of hepatic VOD, with a provision for patients enrolled on the control arm to receive treatment doses of defibrotide upon development of VOD. The study was initiated on the basis of prior studies suggesting there is a benefit to defibrotide in preventing VOD, the largest of which was a randomized trial in 356 pediatric patients.1 The study was expected to enroll approximately 400 adult and pediatric patients undergoing HSCT who are at high risk or very high risk of developing VOD with the potential to increase to 600 patients based on an adaptive design. High-risk or very high-risk patients are identified based on the regimen required to prepare them for HSCT, as well as their prior medical history and concomitant disease. The adaptive design allowed for an interim analysis with pre-defined stopping points for early success or futility as well as the option to increase enrollment up to a maximum of 600 patients if needed to preserve the statistical power of the study.
For patients randomized to receive defibrotide prophylaxis, defibrotide was administered starting within 24 hours before the start of the conditioning regimen for a recommended minimum of 21 days and ending no later than Day +30 post HSCT.
About Defitelio® (defibrotide sodium)
Please see full U.S. Prescribing Information for Defitelio.
▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system found under section 4.8 of the SmPC.
HSCT is an aggressive, potentially curative procedure to treat patients with malignant and non-cancerous hematologic disorders such as leukemia, lymphoma and aplastic anemia, and congenital immunodeficiency and autoimmune disorders.2 VOD is a rare complication of HSCT, which occurs in approximately 9-14% of HSCT patients.3,4 Hepatic VOD, also known as sinusoidal obstruction syndrome, is an early and potentially life-threatening complication affecting the sinusoidal endothelial cells of the liver, which can typically occur within the first 21 days following HSCT.5,6 Hepatic VOD progresses to multi-organ dysfunction in approximately 30-50% of cases.6 VOD with multi-organ dysfunction (MOD) is associated with an overall mortality (death) rate of 84%.4 MOD is characterized by the presence of renal or pulmonary dysfunction.7,8 VOD is often characterized by sudden weight gain, hepatomegaly (abnormally enlarged liver), and elevated bilirubin.7,8
- Corbacioglu, S. et al. (2012). Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial.
Lancet( London, England), [online] 379(9823), pp.1301–1309. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22364685 [Accessed 29 Apr. 2020].
- Defitelio (defibrotide sodium) [package insert].
Palo Alto, CA: Jazz Pharmaceuticals; March 30, 2016.
- Ikehara S. New strategies for BMT and organ transplantation. Int J Hematol. 2002;76(Suppl 1):161-4.
- Coppell JA, Richardson PG, Soiffer R, et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant. 2010;16(2):157-168.
- Tsirigotis PD, Resnick IB, Avni B, et al. Incidence and risk factors for moderate-to-severe veno-occlusive disease of the liver after allogeneic stem cell transplantation using a reduced intensity conditioning regimen. Bone Marrow Transplant. 2014;49(11):1389-1392.
- Carreras E, Díaz-Beyá M, Rosiñol L, et al. The incidence of veno-occlusive disease following allogeneic hematopoietic stem cell transplantation has diminished and the outcome improved over the last decade. Biol Blood Marrow Transplant. 2011;17(11):1713-1720.
- Carreras E. How I manage sinusoidal obstruction syndrome after haematopoietic cell transplantation. Brit J Haematol. 2015 Feb.; 168 (4); 481-91.
- Mohty M, Malard F, Abecassis M, et al. Sinusoidal obstruction syndrome/veno‐occlusive disease: current situation and perspectives—a position statement from the
European Society for Blood and Marrow Transplantation(EBMT). Bone Marrow Transplant. 2015;50(6):781‐789.
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