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

ABSTRACT: Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (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 safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar 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 trial was registered at www.clinicaltrials.gov as #.

SUBMITTER: Richardson PG

PROVIDER: S-EPMC4817309 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Richardson Paul G PG Riches Marcie L ML Kernan Nancy A NA Brochstein Joel A JA Mineishi Shin S Termuhlen Amanda M AM Arai Sally S Grupp Stephan A SA Guinan Eva C EC Martin Paul L PL Steinbach Gideon G Krishnan Amrita A Nemecek Eneida R ER Giralt Sergio S Rodriguez Tulio T Duerst Reggie R Doyle John J Antin Joseph H JH Smith Angela A Lehmann Leslie L Champlin Richard R Gillio Alfred A Bajwa Rajinder R D'Agostino Ralph B RB Massaro Joseph J Warren Diane D Miloslavsky Maja M Hume Robin L RL Iacobelli Massimo M Nejadnik Bijan B Hannah Alison L AL Soiffer Robert J RJ

Blood 20160129 13

Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (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 safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced M ...[more]

PMID: 26825712

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Project description:Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT) that is traditionally diagnosed using Baltimore or modified Seattle criteria. Whereas the Baltimore criteria require the presence of hyperbilirubinemia (bilirubin ≥2 mg/dL) for a diagnosis of VOD/SOS, the modified Seattle criteria do not. Before approval by the US Food and Drug Administration, defibrotide was available in the United States through an expanded-access study (T-IND). The T-IND protocol initially required post-HCT diagnosis of VOD/SOS by the Baltimore criteria or biopsy but was later amended to include patients diagnosed using the modified Seattle criteria. This post hoc analysis examined the incidence of VOD/SOS with a bilirubin level <2 mg/dL before and after Day 21 post-HCT in T-IND patients enrolled following the amendment allowing for diagnosis by the modified Seattle criteria. Survival of adult and pediatric patients with or without hyperbilirubinemia and with or without multiorgan dysfunction (MOD) was also evaluated. Of 803 post-HCT patients with VOD/SOS enrolled following the protocol amendment, 181 (23%) had a bilirubin level <2 mg/dL and would not have been diagnosed if hyperbilirubinemia was required. The bilirubin level at diagnosis was <2 mg/dL in 165 of 331 patients (50%) diagnosed by the modified Seattle criteria and in 16 of 23 patients (70%) diagnosed by biopsy. VOD/SOS with a bilirubin level <2 mg/dL was more common in pediatric patients (29%), although it also occurred in adult patients (15%). Patients with hyperbilirubinemia had lower Day 100 survival (54% versus 87% in patients with bilirubin <2 mg/dL) and a higher incidence of MOD (41% versus 26% in patients with bilirubin <2 mg/dL). The incidence of treatment-emergent adverse events and serious adverse events was lower in patients with a bilirubin level <2 mg/dL. These results indicate that anicteric VOD/SOS occurs in both adult and pediatric patients post-HCT and can be diagnosed before and after Day 21 in both groups. The worse survival in patients with bilirubin ≥2 mg/dL suggests that requiring hyperbilirubinemia may result in a progressed disease stage associated with worse outcomes. Taken together, these results highlight the importance of awareness and the possibility of VOD/SOS in the absence of elevated bilirubin level.

Project description:Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication that occurs after hematopoietic cell transplantation (HCT). The mortality associated with untreated VOD/SOS with multiorgan dysfunction (MOD) has been reported to be >80%. The recommended dose of defibrotide is 6.25 mg/kg every 6 hours, administered as a 2-hour i.v. infusion, for a minimum of 21 days or until resolution of VOD/SOS signs and symptoms. The objective of this analysis was to evaluate the time to complete response (CR) in patients with post-HCT VOD/SOS treated with defibrotide. The time to defibrotide discontinuation due to a CR served as a surrogate for time to CR in an expanded access study (T-IND; ClinicalTrials.gov NCT00628498; n = 1000), and was analyzed separately from the time to CR data pooled from a phase 2 randomized dose-finding study (NCT00003966; n = 74 patients who received 25 mg/kg/day) and a phase 3 historically controlled study (NCT00358501; n = 102). For all studies, a CR was defined as total serum bilirubin <2 mg/dL with resolution of VOD/SOS-related MOD (renal and/or pulmonary dysfunction); the phase 2 study also required resolution of central nervous system dysfunction. In the T-IND, 390 patients discontinued treatment due to a CR and had sufficient data for analysis. The median time to discontinuation was 22 days (range, 2 to 64 days). Discontinuation due to CR occurred beyond 21 days in 235 patients (60%) and beyond 28 days in 57 patients (15%). The pooled phase 2 and 3 studies included 60 patients who achieved a CR, with a median time to CR of 24.5 days (range, 7 to 123 days). A CR was achieved beyond 21 days in 32 patients (53%) and beyond 28 days in 24 patients (40%). The Kaplan-Meier estimate of day +100 survival rate was substantially higher in patients who discontinued due to a CR compared with those who did not (92.5% versus 37.3%). Treatment-emergent adverse events occurred in 185 of 390 patients (47%) who discontinued due to a CR in the T-IND and in 55 of 60 patients (92%) who achieved a CR in the pooled phase 2 and 3 studies, and rates did not differ according to duration of treatment (≤21 days versus >21 days). Taken together, these results highlight the importance of continued defibrotide therapy until resolution of VOD/SOS signs and symptoms, as currently indicated in the approved product labels, which may occur beyond the recommended minimum of 21 days.

Dataset Information

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

Publications

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

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