Very early administration of progesterone for acute traumatic brain injury

for the NETT Investigators

Research output: Contribution to journalArticle

237 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2457-2466
Number of pages10
JournalNew England Journal of Medicine
Volume371
Issue number26
DOIs
StatePublished - Dec 25 2014

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Brain Injuries
Progesterone
Placebos
Wounds and Injuries
Clinical Trials
Confidence Intervals
Medical Futility
Glasgow Outcome Scale
Phlebitis
Thrombophlebitis
Glasgow Coma Scale
Injury Severity Score
Motor Vehicles
Random Allocation
Traumatic Brain Injury
Consciousness
Nervous System
Multicenter Studies
Accidents
Cause of Death

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Very early administration of progesterone for acute traumatic brain injury. / for the NETT Investigators.

In: New England Journal of Medicine, Vol. 371, No. 26, 25.12.2014, p. 2457-2466.

Research output: Contribution to journalArticle

for the NETT Investigators. / Very early administration of progesterone for acute traumatic brain injury. In: New England Journal of Medicine. 2014 ; Vol. 371, No. 26. pp. 2457-2466.
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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.",
author = "{for the NETT Investigators} and Wright, {David W.} and Yeatts, {Sharon D.} and Robert Silbergleit and Palesch, {Yuko Y.} and Hertzberg, {Vicki S.} and Michael Frankel and Goldstein, {Felicia C.} and Caveney, {Angela F.} and Harriet Howlett-Smith and Bengelink, {Erin M.} and Manley, {Geoffrey T.} and Merck, {Lisa H.} and Janis, {L. Scott} and Barsan, {William G.} and Wright, {David W.} and Michael Frankel and Merck, {Lisa H.} and Espinoza, {Tamara R.} and Salomone, {Jeffrey P.} and Dhall, {Sanjay S.} and Hudgins, {Patricia A.} and Allen, {Jason W.} and Felicia Goldstein and Vicki Hertzberg and Rogers, {Susan D.} and {Marie Calcaterra}, Anna and Harriet Howlett-Smith and Bethany Lane and Lunney, {Michael P.} and {Renee Cook}, N. and Alex Hall and Andy Hall and Andrea McDougal and Anuradha Subramanian and Gustavo Pradilla and Stein, {Donald G.} and Robert Silbergleit and Barsan, {William G.} and Arthur Pancioli and Daniel Lowenstein and Meurer, {William J.} and Morgenstern, {Lewis B.} and Valerie Stevenson and Erin Bengelink and Deneil Harney and {De Yampert}, Andrace and Samkeliso Mawocha and Joy Pinkerton and Angela Caveney and Timothy Fabian",
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TY - JOUR

T1 - Very early administration of progesterone for acute traumatic brain injury

AU - for the NETT Investigators

AU - Wright, David W.

AU - Yeatts, Sharon D.

AU - Silbergleit, Robert

AU - Palesch, Yuko Y.

AU - Hertzberg, Vicki S.

AU - Frankel, Michael

AU - Goldstein, Felicia C.

AU - Caveney, Angela F.

AU - Howlett-Smith, Harriet

AU - Bengelink, Erin M.

AU - Manley, Geoffrey T.

AU - Merck, Lisa H.

AU - Janis, L. Scott

AU - Barsan, William G.

AU - Wright, David W.

AU - Frankel, Michael

AU - Merck, Lisa H.

AU - Espinoza, Tamara R.

AU - Salomone, Jeffrey P.

AU - Dhall, Sanjay S.

AU - Hudgins, Patricia A.

AU - Allen, Jason W.

AU - Goldstein, Felicia

AU - Hertzberg, Vicki

AU - Rogers, Susan D.

AU - Marie Calcaterra, Anna

AU - Howlett-Smith, Harriet

AU - Lane, Bethany

AU - Lunney, Michael P.

AU - Renee Cook, N.

AU - Hall, Alex

AU - Hall, Andy

AU - McDougal, Andrea

AU - Subramanian, Anuradha

AU - Pradilla, Gustavo

AU - Stein, Donald G.

AU - Silbergleit, Robert

AU - Barsan, William G.

AU - Pancioli, Arthur

AU - Lowenstein, Daniel

AU - Meurer, William J.

AU - Morgenstern, Lewis B.

AU - Stevenson, Valerie

AU - Bengelink, Erin

AU - Harney, Deneil

AU - De Yampert, Andrace

AU - Mawocha, Samkeliso

AU - Pinkerton, Joy

AU - Caveney, Angela

AU - Fabian, Timothy

PY - 2014/12/25

Y1 - 2014/12/25

N2 - 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.

AB - 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.

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U2 - 10.1056/NEJMoa1404304

DO - 10.1056/NEJMoa1404304

M3 - Article

VL - 371

SP - 2457

EP - 2466

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 26

ER -