UNASSIGNED: Since the first pioneering studies in the 1990s, a large number of experimental animal studies have demonstrated the neuroprotective efficacy of @entity1420 for @entity75 , including @entity131 ( @entity131 ). In addition, this @entity479 has major assets: it easily crosses the blood-brain-barrier, rapidly diffuses throughout the brain and exerts multiple beneficial effects by acting on many molecular and cellular targets. Moreover, @entity1420 therapies are well tolerated. Notably, increased brain levels of @entity1420 are part of endogenous neuroprotective responses to injury. The hormone thus emerged as a particularly promising protective candidate for @entity131 and @entity64 @entity1 . The positive outcomes of small Phase 2 trials aimed at testing the safety and potential protective efficacy of @entity1420 in @entity131 @entity1 then provided support and guidance for two large, multicenter, randomized and placebo-controlled Phase 3 trials, with more than 2000 @entity131 @entity1 enrolled. The negative outcomes of both trials, named ProTECT III and SyNAPSE, came as a big disappointment. If these trials were successful, @entity1420 would have become the first efficient neuroprotective drug for brain-injured @entity1 . Thus, @entity1420 has joined the numerous neuroprotective candidates that have failed in clinical trials. The aim of this review is a reappraisal of the preclinical animal studies, which provided the proof of concept for the clinical trials, and we critically examine the design of the clinical studies. We made efforts to present a balanced view of the strengths and limitations of the translational studies and of some serious issues with the clinical trials. We place particular emphasis on the translational value of animal studies and the relevance of @entity131 biomarkers. The probability of failure of ProTECT III and SyNAPSE was very high, and we present them within the broader context of other unsuccessful trials.

XXXX neuroprotection: The background of clinical trial failure.

@entity1 :: ('9606', 'Species') :: ['patients'] @entity131 :: ('MESH:D001930', 'Disease') :: ['TBI', 'traumatic brain injury'] @entity64 :: ('MESH:D020521', 'Disease') :: ['stroke'] @entity1420 :: ('MESH:D011374', 'Chemical') :: ['progesterone'] @entity75 :: ('MESH:D001927', 'Disease') :: ['brain disorders'] @entity479 :: ('D013256', 'Chemical') :: ['steroid']
@entity1420 :: (MESH:D011374,Chemical) :: ['Progesterone']
