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N Engl J Med. 2014 Dec 25;371(26):2467-76. doi: 10.1056/NEJMoa1411090. Epub 2014 Dec 10.

A clinical trial of progesterone for severe traumatic brain injury.

Collaborators (160)

Marmarou A, Maas AI, Narayan R, Skolnick BE, Ward J, Stocchetti N, Dearden NM, Clarence-Smith K, Genazzani AR, Grady MS, Steyerberg EW, Okonkwo D, Grieve G, Zaaroor M, Levi L, Smrcka M, May A, Pachl J, Manji M, Chen J, Pichon N, Lobato RD, Norasetthada T, Puybasset L, Petit L, Meisel H, Fakhry S, Wilberger J, Sahuquillo J, Rabb C, Walsh J, Mokry M, Yutthakasemsunt S, Huynh T, Rumana C, Audibert G, Citerio G, Agazzi S, Gruen J, O'Leary S, Ransom K, Trimmel H, Turner M, Zucker L, Umansky F, Nardi G, Dominguez JI, Zauberman J, Claridge J, Bulters D, Mace JC, McCarthy M, Colpaert K, Ratanalert S, Couture D, Choi K, Verma V, Cheng Y, Wang E, Rosen C, Medow J, Patterson L, Alberico A, Avila RA, Vega E, Unterberg A, Stocchetti N, Zhou L, Wong S, Beretta L, Laskowitz D, Vincent JL, Dominguez-Roldán J, Molina JM, Wang Z, Coimbra R, German J, Emhoff T, Boakye M, Surdell DL, García E, Leone M, Nimsky C, Sandesc D, Nagy L, Badenes R, Öhman J, Barnes S, Jacoby M, Shillinglaw W, Orlandi C, Vander Laenen M, Grigoriev R, Rohde V, Vajkoczy P, Raventós AA, Minguillón MA, Oram J, Kuang Y, Chou N, Grindlinger G, Rodgers R, Tinti M, Nagy K, Pellegrini J, George R, Brevard SB, Barbozà A, Payen JF, Troubleyn J, Lavicka P, van der Naalt J, Spoelstra-de Man A, Molina JA, Miranda P, Lopez PM, Wright J, Thambinayagam H, Cheng W, Fulda G, Garrote M, Schmutzhard E, Depreitere B, Greiner C, Zacharowski K, Nevo M, Kang D, Yu R, Alias A, Nor MM, Espinosa J, Shaffrey M, Beauchamp K, Faber T, Dailler F, Cejpek P, Belkin S, Sardaryan I, Kobyakov G, Orel V, Weber F, Procaccio F, Della Corte F, Barzó P, Laha S, Zhang B, Cheang V, Arnold P, Badr A, Andersen B, Putnam A 2nd, Murali R, Videtta W, Regelsberger J, Rappaport ZH, Büki A, Mendiluce RM, Kumar D, Ng I, Tu YK.

Author information

1
From the Department of Neurosurgery, Cushing Neuroscience Institute, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY (B.E.S., R.K.N.); the Department of Neurosurgery, University Hospital Antwerp and University of Antwerp, Edegem, Belgium (A.I.M.); BHR Pharma, Herndon (R.G.H., T.M., N.R.N.), and the Department of Neurosurgery, Virginia Commonwealth University, Richmond (J.D.W.) - both in Virginia; and the Department of Physiopathology and Transplantation, Milan University and Neuro Intensive Care Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Cà Granda Ospedale Maggiore Policlinico, Milan (N.S.).

Abstract

BACKGROUND:

Progesterone has been associated with robust positive effects in animal models of traumatic brain injury (TBI) and with clinical benefits in two phase 2 randomized, controlled trials. We investigated the efficacy and safety of progesterone in a large, prospective, phase 3 randomized clinical trial.

METHODS:

We conducted a multinational placebo-controlled trial, in which 1195 patients, 16 to 70 years of age, with severe TBI (Glasgow Coma Scale score, ≤8 [on a scale of 3 to 15, with lower scores indicating a reduced level of consciousness] and at least one reactive pupil) were randomly assigned to receive progesterone or placebo. Dosing began within 8 hours after injury and continued for 120 hours. The primary efficacy end point was the Glasgow Outcome Scale score at 6 months after the injury.

RESULTS:

Proportional-odds analysis with covariate adjustment showed no treatment effect of progesterone as compared with placebo (odds ratio, 0.96; confidence interval, 0.77 to 1.18). The proportion of patients with a favorable outcome on the Glasgow Outcome Scale (good recovery or moderate disability) was 50.4% with progesterone, as compared with 50.5% with placebo. Mortality was similar in the two groups. No relevant safety differences were noted between progesterone and placebo.

CONCLUSIONS:

Primary and secondary efficacy analyses showed no clinical benefit of progesterone in patients with severe TBI. These data stand in contrast to the robust preclinical data and results of early single-center trials that provided the impetus to initiate phase 3 trials. (Funded by BHR Pharma; SYNAPSE ClinicalTrials.gov number, NCT01143064.).

PMID:
25493978
DOI:
10.1056/NEJMoa1411090
[Indexed for MEDLINE]
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