Skip to main content
SpringerLink
Log in

High Dose Deferoxamine in Intracerebral Hemorrhage (Hi-Def) Trial: Rationale, Design, and Methods

  • TAKE A CLOSER LOOK AT TRIALS
  • Published:
Neurocritical Care Aims and scope Submit manuscript

Abstract

Background

Hemoglobin degradation products, in particular iron, have been implicated in secondary neuronal injury following intracerebral hemorrhage (ICH). The iron chelator Deferoxamine Mesylate (DFO) exerts diverse neuroprotective effects, reduces perihematoma edema (PHE) and neuronal damage, and improves functional recovery after experimental ICH. We hypothesize that treatment with DFO could minimize neuronal injury and improve outcome in ICH patients. As a prelude to test this hypothesis, we conducted a Phase I, open-label study to determine the tolerability, safety, and maximum tolerated dose (MTD) of DFO in patients with ICH. Intravenous infusions of DFO in doses up to 62 mg/kg/day (up to a maximum of 6000 mg/day) were well-tolerated and did not seem to increase serious adverse events (SAEs) or mortality. We have initiated a multi-center, double-blind, randomized, placebo-controlled, Phase II clinical trial (High Dose Deferoxamine [HI-DEF] in Intracerebral Hemorrhage) to determine if it is futile to move DFO forward to Phase III efficacy evaluation.

Methods

We will randomize 324 subjects with spontaneous ICH to either DFO at 62 mg/kg/day (up to a maximum daily dose of 6000 mg/day) or saline placebo, given by intravenous infusion for 5 consecutive days. Treatment will be initiated within 24 hours after ICH symptom onset. All subjects will be followed for 3 months and will receive standard of care therapy while participating in the study. At 3 months, the proportion of DFO-treated subjects with a good clinical outcome, assessed by modified Rankin Scale, will be compared to the placebo proportion in a futility analysis.

Conclusions

The Hi-Def trial is expected to advance our understanding of the pathopgysiology of secondary neuronal injury in ICH and will provide a crucial “Go/No Go” signal as to whether a Phase III trial to investigate the efficacy of DFO is warranted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Castillo J, Davalos A, Alvarez-Sabin J, Pumar JM, Leira R, Silva Y, Montaner J, et al. Molecular signatures of brain injury after intracerebral hemorrhage. Neurology. 2002;58(4):624–9.

    Article  PubMed  CAS  Google Scholar 

  2. He Y, Wan S, Hua Y, Keep RF, Xi G. Autophagy after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab. 2008;28(5):897–905.

    Article  PubMed  CAS  Google Scholar 

  3. Huang FP, Xi G, Keep RF, Hua Y, Nemoianu A, Hoff JT. Brain edema after experimental intracerebral hemorrhage: role of hemoglobin degradation products. J Neurosurg. 2002;96(2):287–93.

    Article  PubMed  Google Scholar 

  4. Wagner KR, Sharp FR, Ardizzone TD, Lu A, Clark JF. Heme and iron metabolism: role in cerebral hemorrhage. J Cereb Blood Flow Metab. 2003;23(6):629–52.

    Article  PubMed  CAS  Google Scholar 

  5. Selim M. Deferoxamine mesylate: a new hope for intracerebral hemorrhage: from bench to clinical trials. Stroke. 2009;40(3 Suppl):S90–1.

    Article  PubMed  CAS  Google Scholar 

  6. Nakamura T, Keep RF, Hua Y, Schallert T, Hoff JT, Xi G. Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage. J Neurosurg. 2004;100(4):672–8.

    Article  PubMed  CAS  Google Scholar 

  7. Gu Y, Hua Y, Keep RF, Morgenstern LB, Xi G. Deferoxamine reduces intracerebral hematoma-induced iron accumulation and neuronal death in piglets. Stroke. 2009;40:2241–3.

    Article  PubMed  CAS  Google Scholar 

  8. Okauchi M, Hua Y, Keep RF, Morgenstern LB, Xi G. Effects of deferoxamine on intracerebral hemorrhage-induced brain injury in aged rats. Stroke. 2009;40:1858–63.

    Article  PubMed  CAS  Google Scholar 

  9. Wan S, Hua Y, Keep RF, Hoff JT, Xi G. Deferoxamine reduces CSF free iron levels following intracerebral hemorrhage. Acta Neurochir Suppl. 2006;96:199–202.

    Article  PubMed  CAS  Google Scholar 

  10. Messer JG, Cooney PT, Kipp DE. Iron chelator deferoxamine alters iron-regulatory genes and proteins and suppresses osteoblast phenotype in fetal rat calvaria cells. Bone. 2010;46(5):1408–15.

    Article  PubMed  CAS  Google Scholar 

  11. Ratan RR, Siddiq A, Aminova L, Langley B, McConoughey S, Karpisheva K, et al. Small molecule activation of adaptive gene expression: tilorone or its analogs are novel potent activators of hypoxia inducible factor-1 that provide prophylaxis against stroke and spinal cord injury. Ann N Y Acad Sci. 2008;1147:383–94.

    Article  PubMed  CAS  Google Scholar 

  12. Wan S, Zhan R, Zheng S, Hua Y, Xi G. Activation of c-Jun-N-terminal kinase in a rat model of intracerebral hemorrhage: the role of iron. Neurosci Res. 2009;63:100–5.

    Article  PubMed  CAS  Google Scholar 

  13. Tanji K, Imaizumi T, Matsumiya T, Itaya H, Fujimoto K, Cui X, et al. Desferrioxamine, an iron chelator, upregulates cyclooxygenase-2 expression and prostaglandin production in a human macrophage cell line. Biochim Biophys Acta. 2001;1530(2–3):227–35.

    PubMed  CAS  Google Scholar 

  14. Suri MF, Suarez JI, Rodrigue TC, Zaidat OO, Vazquez G, Wensel A, et al. Effect of treatment of elevated blood pressure on neurological deterioration in patients with acute intracerebral hemorrhage. Neurocrit Care. 2008;9(2):177–82.

    Article  PubMed  Google Scholar 

  15. Selim M, Yeatts S, Goldstein JN, Gomes J, Greenberg S, Morgenstern LB, et al. Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage. Stroke. 2011;42(11):3067–74.

    Article  PubMed  CAS  Google Scholar 

  16. Haley EC Jr, Thompson JL, Levin B, Davis S, Lees KR, Pittman JG, et al. Gavestinel does not improve outcome after acute intracerebral hemorrhage: an analysis from the GAIN International and GAIN Americas studies. Stroke. 2005;36(5):1006–10.

    Article  PubMed  CAS  Google Scholar 

  17. Lyden PD, Shuaib A, Lees KR, Davalos A, Davis SM, Diener HC, et al. Safety and tolerability of NXY-059 for acute intracerebral hemorrhage: the CHANT Trial. Stroke. 2007;38(8):2262–9.

    Article  PubMed  CAS  Google Scholar 

  18. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005;352(8):777–85.

    Article  PubMed  CAS  Google Scholar 

  19. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer M, et al. Efficacy and safety of recombinant activated factor VII for acute ICH. N Engl J Med. 2008;358:2127–37.

    Article  PubMed  CAS  Google Scholar 

  20. Chow S, Shao J, Wang H. Sample size calculations in clinical research. Boca Raton: CRC press; 2003.

    Google Scholar 

  21. Friedman LM, Furberg CD, DeMets DL. Fundamentals of clinical trials. 3rd ed. New York: Springer; 1998.

    Book  Google Scholar 

  22. McCarron MO, Hoffmann KL, DeLong DM, Gray L, Saunders AM, Alberts MJ. Intracerebral hemorrhage outcome: apolipoprotein E genotype, hematoma, and edema volumes. Neurology. 1999;53(9):2176–9.

    Article  PubMed  CAS  Google Scholar 

  23. Sansing LH, Messe SR, Cucchiara BL, Lyden PD, Kasner SE. Anti-adrenergic medications and edema development after intracerebral hemorrhage. Neurocrit Care. 2011;14(3):395–400.

    Article  PubMed  CAS  Google Scholar 

  24. Inaji M, Tomita H, Tone O, Tamaki M, Suzuki R, Ohno K. Chronological changes of perihematomal edema of human intracerebral hematoma. Acta Neurochir Suppl. 2003;86:445–8.

    PubMed  CAS  Google Scholar 

  25. Zazulia AR, Diringer MN, Derdeyn CP, Powers WJ. Progression of mass effect after intracerebral hemorrhage. Stroke. 1999;30(6):1167–73.

    Article  PubMed  CAS  Google Scholar 

  26. Venkatasubramanian C, Mlynash M, Finley-Caulfield A, Eyngorn I, Kalimuthu R, Snider RW, Wijman CA. Natural history of perihematomal edema after intracerebral hemorrhage measured by serial magnetic resonance imaging. Stroke. 2011;42(1):73–80.

    Article  PubMed  Google Scholar 

  27. Macdonald RL, Marton LS, Andrus PK, Hall ED, Johns L, Sajdak M. Time course of production of hydroxyl free radical after subarachnoid hemorrhage in dogs. Life Sci. 2004;75(8):979–89.

    Article  PubMed  CAS  Google Scholar 

  28. Wu J, Hua Y, Keep RF, Nakamura T, Hoff JT, Xi G. Iron and iron-handling proteins in the brain after intracerebral hemorrhage. Stroke. 2003;34(12):2964–9.

    Article  PubMed  CAS  Google Scholar 

  29. Palesch Y, Tilley B, Sackett D, Johnston K, Woolson R. Applying a phase II futility study design to therapeutic stroke trials. Stroke. 2005;36:2410–4.

    Article  PubMed  Google Scholar 

  30. Forstmeier W, Schielzeth H. Cryptic multiple hypotheses testing in linear models: overestimated effect sizes and the winner’s curse. Behav Ecol Sociobiol. 2011;65(1):47–55.

    Article  PubMed  Google Scholar 

  31. Davis SM, Broderick J, Hennerici M, Brun NC, Diringer MN, Mayer SA, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology. 2006;66(8):1175–81.

    Article  PubMed  CAS  Google Scholar 

  32. Russell MW, Joshi VA, Neumann PJ, Boulanger L, Menzin J. Predictors of hospital length of stay in patients with ICH. Neurology. 2006;67:1279–81.

    Article  PubMed  CAS  Google Scholar 

  33. Fisher M, Hanley DF, Howard G, Jauch EC. Warach S; STAIR Group. Recommendations from the STAIR V meeting on acute stroke trials, technology and outcomes. Stroke. 2007;38(2):245–8.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by the National Institute of Health (Grant # U01 NS074425).

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Data Coordination Unit, Department of Public Health Sciences, College of Medicine, Medical University of South Carolina, Charleston, SC, USA

    Sharon D. Yeatts & Yuko Y. Palesch

  2. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

    Claudia S. Moy

  3. Stroke Division, Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Palmer 127, Boston, MA, 02215, USA

    Magdy Selim

Authors
  1. Sharon D. Yeatts
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuko Y. Palesch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claudia S. Moy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Magdy Selim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Magdy Selim.

Additional information

ClinicalTrials.gov Identifier: NCT01662895.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yeatts, S.D., Palesch, Y.Y., Moy, C.S. et al. High Dose Deferoxamine in Intracerebral Hemorrhage (Hi-Def) Trial: Rationale, Design, and Methods. Neurocrit Care 19, 257–266 (2013). https://doi.org/10.1007/s12028-013-9861-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12028-013-9861-y

Keywords

Search

Navigation