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N Engl J Med. 2014 Dec 25;371(26):2457-66. doi: 10.1056/NEJMoa1404304. Epub 2014 Dec 10.

Very early administration of progesterone for acute traumatic brain injury.

Collaborators (299)

Wright DW, Frankel M, Merck LH, Espinoza TR, Salomone JP, Dhall SS, Hudgins PA, Allen JW, Goldstein F, Hertzberg V, Rogers SD, Calcaterra AM, Howlett-Smith H, Lane B, Lunney MP, Cook N, Hall A, Hall A, McDougal A, Subramanian A, Pradilla G, Stein DG, Silbergleit R, Barsan WG, Pancioli A, Lowenstein D, Meurer WJ, Morgenstern LB, Stevenson V, Bengelink E, Harney D, De Yampert A, Mawocha S, Pinkerton J, Caveney A, Yeatts S, Palesch Y, Zhao W, Pauls Q, Pauls K, Dillon CR, Conner C, Henry A, Patel K, Simons JL, Manley G, Aarabi B, Harris O, Hemphill C, LeRoux P, Narayan R, Okonkwo DO, Pascual J, Salomone JP, Schwab W, Valadka A, Wright DW, Janis S, Conwit R, Denninghoff K, Friese R, Zabramski J, Oneill PJ, Feinstein A, Yonas H, Stasinski G, Barnhart B, Wood L, Haney S, Livergood DL, Burlbaw B, Wright DW, Frankel M, Croce MA, McCafferty RR, Lunney MP, Panzer-Baggett S, Warren JB, Hall AJ, McDougal AG, Cook N, Wilson S, Waddle-Smith L, Barrow S, Pitotti R, Espinoza TR, Hudgins PA, Allen JW, Subramanian A, Fabian TC, Muhlbauer MS, Hilliard MW, Bebarta VS, Gunst MA, Amador RR, Lo IW, Quinn JV, Lee M, Blumenfeld K, Venkatasubramanian C, Visweswaran A, Mann R, Harris OA, D'Souza P, Spain DA, Hirsch K, Torres R, Kline R, Benford J, Traver C, Yeh D, Pancioli A, Shutter L, Johannigman J, Bonomo J, Stark S, Ewing I, Waymeyer P, Schmit P, Adeoye O, Mcmullan J, Robinson B, Andaluz N, Newman P, Biros M, Irwin ED, Dries DJ, Rockswold G, Miller K, Sargent C, Reicks P, Wewerka SS, Salzman J, Zagar A, Kragness K, Hildebrandt D, Scherber J, Bennett BA, Zwank MD, Jones E, Milling TJ Jr, Ottman M, Mendoza-Moore M, LaChance L, King B, Doshi P, Aufderheide TP, Lynch J, Torbey M, Boettcher M, Bialkowski W, Brandt JT Jr, Burpee K, Gauger S, Herdeman C, Hermanson B, Hessenthaler A, Jasti J, McCormick K, Mena M, Morrow K, Price G, Sandoval C, Qaisar T, Quering B, Zellner S, Zeisse M, Brasel K, Maiman D, Zaidat OO, Baren JM, Portner M, Merck LH, Sarani B, Stehly C, Bertsch K, Garey C, Lamond K, Durinka JB, Gromek S, Jochym N, Pascual JL, Kasner SE, LeRoux PD, Schuster J, Gentile NT, Saks M, Fisher MA, Jallo J, Timmons S, McNelis PM, Reimer H, Nocera R, Campbell NA, Gardner K, Weaver M, Goldberg A, Wang A, Healy M, Warden CR, Prewitt L, Hilliard C, Schreiber M, Lowe R, Ornato JP, Mathern BE, Mathern K, Merchant RE, Feeser VR, Dhindsa HS, Leahman CE, Humphries RL, Short J, Dechtenberg L, Taylor DG, Pettigrew L, Carter CT, Desai S, Welch RD, Swor RA, Mika VH, Paternoster RA, Norris GM, Coplin WM, Pearson C, O'Neil BJ, Ayaz SI, Clark CL, Sawyer KN, Rae RW Jr, Wiener MA, Grace HA, Hemphill J 3rd, Meeker M, Duncan J, Alvarado E, Casey S, Lauder I, Manley G, Lewandowski CA, Miller JB, Borgialli DA, Lundell AM, Baker A, LaChance J, Falvo A, Abdelhak T, Vohra T, Nagarwala J, Fowkes R, Claassen J, Rosengart A, Falo M, Fokken T, Agarwal S, Lord A, Connolly E, Velander A, Pavol M, Zammit C, Foreman B, Mayer S, Stern B, Eisenberg H, Aldrich C, Ganley V, Aarabi B, Goldstein JN, Rosenthal ES, Burke P, Nentwich LM, Howell M, Mitchell P, Riklin E, Feldman J, Levine SR, Jain A, Zelonis S, Bushey M, Sinert R, Ver Halen N, Rojas-Soto D, Martindale J, Paladino L, Legome E, Valsamis LH, Brandler E, Chatterjee P, Torbey M, Green A, Angelos M, Caterino J, Elder J, Steinberg S, Callaway C, Okonkwo DO, Puccio AM, Shutter LA, Dezfulian C.

Author information

1
From the Departments of Emergency Medicine (D.W.W., H.H.-S.) and Neurology (M.F., F.C.G.), Emory University School of Medicine and Grady Memorial Hospital, and the Department of Biostatistics, Rollins School of Public Health, Emory University (V.S.H.) - all in Atlanta; the Department of Public Health Sciences, Medical University of South Carolina, Charleston (S.D.Y., Y.Y.P.); the Departments of Emergency Medicine (R.S., E.M.B., W.G.B.) and Psychiatry (A.F.C.), University of Michigan, Ann Arbor; the Department of Neurosurgery, University of California, San Francisco, San Francisco (G.T.M.); the Department of Emergency Medicine, Warren Alpert Medical School of Brown University, Providence, RI (L.H.M.); and the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (L.S.J.).

Abstract

BACKGROUND:

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI.

METHODS:

We conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score.

RESULTS:

A total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle accident. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P=0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes.

CONCLUSIONS:

This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900.).

PMID:
25493974
PMCID:
PMC4303469
DOI:
10.1056/NEJMoa1404304
[Indexed for MEDLINE]
Free PMC Article
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