Loading
The primary report of Study 2005-01: 38 percent of transplant patients with severe veno-occlusive disease and organ failure were alive at day 100 on defibrotide, against 25 percent of carefully matched historical controls.
Phase 3 study of defibrotide in patients with established hepatic veno-occlusive disease (sinusoidal obstruction syndrome) and advanced multi-organ failure after haematopoietic stem cell transplantation, a condition with more than 80 percent mortality untreated. Patients (n = 102) given defibrotide 25 mg per kilogram per day were compared with 32 historical controls identified from 6867 medical charts of transplant patients by blinded independent reviewers; baseline characteristics were well balanced.
The primary endpoint was survival at day +100 post-transplant: observed rates were 38.2 percent in the defibrotide group and 25 percent in the controls (23 percent estimated difference; 95.1% CI 5.2 to 40.8; P = .0109, propensity-adjusted analysis). Observed day +100 complete response rates were 25.5 percent for defibrotide and 12.5 percent for controls (19 percent difference; 95.1% CI 3.5 to 34.6; P = .0160). Related adverse events included haemorrhage or hypotension; common haemorrhagic events (pulmonary alveolar 11.8 and 15.6 percent, gastrointestinal 7.8 and 9.4 percent) were similar between groups.
This is the trial behind defibrotide's March 2016 US approval, the only approved treatment for hepatic veno-occlusive disease with organ failure after transplant. The historical-control design was accepted because a randomised trial in a condition this lethal and rare was judged unfeasible; the gain is meaningful but most patients still died.