title: Progesterone neuroprotection: The background of clinical trial failure.
abstract: Since the first pioneering studies in the 1990s, a large number of experimental animal studies have demonstrated the neuroprotective efficacy of progesterone for brain disorders, including traumatic brain injury (TBI). In addition, this steroid 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, progesterone therapies are well tolerated. Notably, increased brain levels of progesterone are part of endogenous neuroprotective responses to injury. The hormone thus emerged as a particularly promising protective candidate for TBI and stroke patients. The positive outcomes of small Phase 2 trials aimed at testing the safety and potential protective efficacy of progesterone in TBI patients then provided support and guidance for two large, multicenter, randomized and placebo-controlled Phase 3 trials, with more than 2000 TBI patients enrolled. The negative outcomes of both trials, named ProTECT III and SyNAPSE, came as a big disappointment. If these trials were successful, progesterone would have become the first efficient neuroprotective drug for brain-injured patients. Thus, progesterone 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 TBI 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.
authors.affiliation: U1195 Inserm and University Paris-Sud and University Paris-Saclay, 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France. Electronic address: michael.schumacher@inserm.fr.
authors.forename: Michael
authors.initials: M
authors.lastname: Schumacher
authors.affiliation: U1195 Inserm and University Paris-Sud and University Paris-Saclay, 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France; Department of Neurology, CHU Bicêtre, 78 rue du Général Leclerc, 94275 Kremlin-Bicêtre, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Denier
authors.affiliation: U1195 Inserm and University Paris-Sud and University Paris-Saclay, 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Oudinet
authors.affiliation: U1195 Inserm and University Paris-Sud and University Paris-Saclay, 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France; Department of Neurology, CHU Bicêtre, 78 rue du Général Leclerc, 94275 Kremlin-Bicêtre, France.
authors.forename: David
authors.initials: D
authors.lastname: Adams
authors.affiliation: U1195 Inserm and University Paris-Sud and University Paris-Saclay, 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France.
authors.forename: Rachida
authors.initials: R
authors.lastname: Guennoun
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D006801:Humans; D023421:Models, Animal; D000066829:Neuroprotection / Q000187:drug effects; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D011374:Progesterone / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D018696:Neuroprotective Agents; D011374:Progesterone
keywords: Animal models; Biomarkers; Clinical trials; Progesterone; Stroke; Translational research; Traumatic brain injury