Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure

Paul G. Richardson, Marcie L. Riches, Nancy A. Kernan, Joel A. Brochstein, Shin Mineishi, Amanda M. Termuhlen, Sally Arai, Stephan A. Grupp, Eva C. Guinan, Paul L. Martin, Gideon Steinbach, Amrita Krishnan, Eneida R. Nemecek, Sergio Giralt, Tulio Rodriguez, Reggie Duerst, John Doyle, Joseph H. Antin, Angela Smith, Leslie Lehmann, Richard Champlin, Alfred Gillio, Rajinder Bajwa, Ralph B. D'Agostino Sr., Joseph Massaro, Diane Warren, Maja Miloslavsky, Robin L. Hume, Massimo Iacobelli, Bijan Nejadnik, Alison L. Hannah and Robert J. Soiffer

Key points

  • Defibrotide improves Day+100 survival and complete response in patients with VOD and multi-organ failure compared with a historical control.

  • The historical control selection methodology offers a novel approach for investigation of a life-threatening orphan disease.


Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated the safety and efficacy of defibrotide in adult and pediatric patients with established hepatic VOD/SOS and advanced MOF. Patients (n=102) given 25 mg/kg/day defibrotide were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by a blinded independent medical review committee. Baseline characteristics between groups were well balanced. The primary objective was to compare survival at Day+100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25.0% in the control group (estimated difference of 23.0%; 95.1% confidence interval [CI] 5.2%-40.8%; P=.0109, using a propensity-adjusted analysis based on 4 prognostic factors of survival). Observed Day+100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% in the controls (19.0% difference using similar methodology; 95.1% CI 3.5-34.6; P=.0160). Defibrotide was generally well-tolerated with manageable toxicity. Related adverse events included hemorrhage or hypotension; there was no difference in the incidence of common hemorrhagic adverse events (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal [7.8% and 9.4%]) between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in Day+100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This study is registered to as NCT00358501.

  • Submitted October 21, 2015.
  • Accepted January 22, 2016.