Clinical Evidence of Progesterone's Neuroprotective Properties

Given the diverse mechanisms thought to be impicated in TBI-associated damage and the data suggesting that progesterone can address multiple mechanisms, progesterone may have a higher likelihood of positively affecting clinical outcomes than mechanistically more limited approaches that have failed, such as magnesium, dexanabinol, hypothermia, Selfotel, tirilizad, Pegsod, triamcinolone, nimodipine, dexamethasone, tromethamine and methylprednisolone.1,2,3

Two Phase 2 clinical trials have been conducted with parenterally-administered progesterone, and these trials have revealed acceptable safety profiles and promising efficacy results in the acute treatment of moderate and severe TBI.4,5

Overall, the use of progesterone in patients who have suffered a severe TBI may provide the following benefits:

  1. Progesterone rapidly enters the brain and reaches equilibrium within an hour6 and intravenous administration of progesterone allows high plasma levels to be achieved within 1 hour after infusion.7
  2. Rapid parenteral administration given to severe/moderate TBI patients within a few hours post injury can significantly improve survival and reduce sustained brain damage as ascertained by the concomitant improvement in functional outcomes.8,9
  3. When progesterone is used as a neuroprotective agent in placebo-controlled TBI clinical trials, limited side effects have been reported.10,11 Moreover, i.v. administration of high doses of progesterone in other fragile patient populations (e.g., cancer patients, extremely preterm infants) also supports the acceptable safety profile of this treatment.12,13,14,15

Given progesterone's potential as an effective pharmacological treatment to improve TBI outcomes, BHR Pharma, LLC initiated SyNAPSE, a global, Phase 3, multi-center pivotal trial in June 2010.

  1. Beauchamp, K., Mutlak, H., Smith, W.R., Shohami, E., and Stahel, P.F. (2008). Mol. Med. 14(11-12), 731-740.
  2. Kazanis, I. (2005). Brain Res. Rev., 50, 377-386.
  3. Tolias, C.M., and Bullock, M.R. (2004). NeuroRx., 1(1), 71-79.
  4. Wright, D.W., Kellermann, A.L., Hertzberg, V.S., Clark, P.L., Frankel, M., Goldstein, F.C., et al. (2007). Ann Emerg Med., 49,391-402.
  5. Xiao, G. et.al. (2008) Critical Care, 12, R61.
  6. Pardridge, W.M. and Mietus, L.J. (1979) J. Clin. Invest. 145(64), 145-154.
  7. Wright, D.W., Ritchie, J.C., Mullins, R.E., Kellerman, A.L., and Denson, D.D. (2005). J Clin Pharmacol., 45, 640-648.
  8. Wright, D.W., Kellermann, A.L., Hertzberg, V.S., Clark, P.L., Frankel, M., Goldstein, F.C., et al. (2007). ProTECT: A randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med., 49, 391-402.
  9. Xiao, G. et.al. (2008) Critical Care, 12, R61.
  10. Wright, D.W., Kellermann, A.L., Hertzberg, V.S., Clark, P.L., Frankel, M., Goldstein, F.C., et al. (2007). Ann Emerg Med., 49, 391-402.
  11. Xiao, G.et.al. (2008) Critical Care, 12, R61.
  12. Aebi, S., Schnider, T.W., Los, G., Heath, D.D, Darrah, D., Kirmani, S. et al. (1999). Cancer Chemother. Pharmacol., 44, 259-265.
  13. Christen, R.D., McClay, E.F., Plaxe, S.C., Yen, S.S., Kim, S., Kirmani S., et al. (1993). J. Clin. Oncol., 11, 2417-2426.
  14. Trotter, A., Maier, L., Grill, H.J., Kohn, T., Heckmann, M., and Pohlandt, F. (1999J. Clin. Endocrinol. Metab., 84, 4531-4535.
  15. Trotter, A., Maier, L., Kron, M., and Pohlandt, F. (2007). Arch. Dis. Child Fetal Neonatal Ed., 92, F94-8.