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

Publication ,  Journal Article
Richardson, PG; Riches, ML; Kernan, NA; Brochstein, JA; Mineishi, S; Termuhlen, AM; Arai, S; Grupp, SA; Guinan, EC; Martin, PL; Steinbach, G ...
Published in: Blood
March 31, 2016

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 #.

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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

March 31, 2016

Volume

127

Issue

13

Start / End Page

1656 / 1665

Location

United States

Related Subject Headings

  • Young Adult
  • Severity of Illness Index
  • Polydeoxyribonucleotides
  • Multiple Organ Failure
  • Middle Aged
  • Male
  • Infant, Newborn
  • Infant
  • Immunology
  • Humans
 

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Richardson, P. G., Riches, M. L., Kernan, N. A., Brochstein, J. A., Mineishi, S., Termuhlen, A. M., … Soiffer, R. J. (2016). Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood, 127(13), 1656–1665. https://doi.org/10.1182/blood-2015-10-676924
Richardson, Paul G., Marcie L. Riches, Nancy A. Kernan, Joel A. Brochstein, Shin Mineishi, Amanda M. Termuhlen, Sally Arai, et al. “Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure.Blood 127, no. 13 (March 31, 2016): 1656–65. https://doi.org/10.1182/blood-2015-10-676924.
Richardson PG, Riches ML, Kernan NA, Brochstein JA, Mineishi S, Termuhlen AM, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016 Mar 31;127(13):1656–65.
Richardson, Paul G., et al. “Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure.Blood, vol. 127, no. 13, Mar. 2016, pp. 1656–65. Pubmed, doi:10.1182/blood-2015-10-676924.
Richardson PG, Riches ML, Kernan NA, Brochstein JA, Mineishi S, Termuhlen AM, Arai S, Grupp SA, Guinan EC, Martin PL, Steinbach G, Krishnan A, Nemecek ER, Giralt S, Rodriguez T, Duerst R, Doyle J, Antin JH, Smith A, Lehmann L, Champlin R, Gillio A, Bajwa R, D’Agostino RB, Massaro J, Warren D, Miloslavsky M, Hume RL, Iacobelli M, Nejadnik B, Hannah AL, Soiffer RJ. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016 Mar 31;127(13):1656–1665.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

March 31, 2016

Volume

127

Issue

13

Start / End Page

1656 / 1665

Location

United States

Related Subject Headings

  • Young Adult
  • Severity of Illness Index
  • Polydeoxyribonucleotides
  • Multiple Organ Failure
  • Middle Aged
  • Male
  • Infant, Newborn
  • Infant
  • Immunology
  • Humans