Very Early Administration of Progesterone for Acute Traumatic Brain Injury
Open accessAbstract
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.).
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The disappointing results of progesterone in Phase III clinical trials has called into question the importance of sex hormones in determining TBI outcome.
“Finally, the disappointing results of progesterone in Phase III clinical trials has called into question the importance of sex hormones in determining TBI outcome. 73,74”
From Sex Differences in Traumatic Brain Injury: What We Know and What We Should Know (2019) · cites this paper as [74]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
ASSESSMENT OF COMA AND IMPAIRED CONSCIOUSNESS
Teasdale, G., & Jennett, B. (1974) · The Lancet · doi:10.1016/s0140-6736(74)91639-0 · Cited by 13,215 · see citing works
ASSESSMENT OF OUTCOME AFTER SEVERE BRAIN DAMAGE A Practical Scale
JENNETT, B. (1975) · The Lancet · doi:10.1016/s0140-6736(75)92830-5 · Cited by 7,501 · see citing works
Family history of subarachnoid haemorrhage: supplemental value of scrutinizing all relatives.
Greebe, P., Bromberg, J. E. C., Rinkel, G. J. E., Algra, A., & van Gijn, J. (1997) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.62.3.273 · Cited by 4,137 · see citing works
The Epidemiology and Impact of Traumatic Brain Injury: A Brief Overview
Langlois, J., Rutland-Brown, W., & Wald, M. (2006) · The journal of head trauma rehabilitation · doi:10.1097/00001199-200609000-00001 · Cited by 3,893 · see citing works
A Multiple Testing Procedure for Clinical Trials
O'Brien, P. C., & Fleming, T. R. (1979) · Biometrics · doi:10.2307/2530245 · Cited by 3,311 · see citing works
WILSON, J. T. L., PETTIGREW, L. E. L., & TEASDALE, G. M. (1998) · Journal of Neurotrauma · doi:10.1089/neu.1998.15.573 · Cited by 2,386 · see citing works
Update of the Stroke Therapy Academic Industry Roundtable Preclinical Recommendations
Fisher, M., Feuerstein, G., Howells, D. W., Hurn, P. D., Kent, T. A., Savitz, S. I., & Lo, E. H. (2009) · Stroke · doi:10.1161/strokeaha.108.541128 · Cited by 1,352 · see citing works
Disability rating scale for severe head trauma: coma to community.
Rappaport, M. B., Hall, K., Hopkins, K. L., Belleza, T., & Cope, D. N. (1982) · PubMed · Cited by 1,093 · see citing works
Maas, A. I. R., Hukkelhoven, C. W. P. M., Marshall, L. F., & Steyerberg, E. W. (2005) · Neurosurgery · doi:10.1227/01.neu.0000186013.63046.6b · Cited by 943 · see citing works
Clinical trials in head injury
Narayan, R. K., Michel, M. E., Ansell, B., Baethmann, A., Biegon, A., Bracken, M. B., Bullock, M. R., Choi, S. C., Clifton, G. L., Contant, C. F., et al. (2002) · Journal of Neurotrauma · doi:10.1089/089771502753754037 · Cited by 913 · see citing works
ProTECT: A Randomized Clinical Trial of Progesterone for Acute Traumatic Brain Injury
Wright, D. W., Kellermann, A. L., Hertzberg, V., Clark, P. L., Frankel, M., Goldstein, F. C., Salomone, J. P., Dent, L. L., Harris, O. A., Ander, D. S., et al. (2006) · Annals of Emergency Medicine · doi:10.1016/j.annemergmed.2006.07.932 · Cited by 599 · see citing works
Self-citationLoane, D. J., & Faden, A. I. (2010) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2010.09.005 · Cited by 574 · see citing works
Xiao, G., Wei, J., Yan, W., Wang, W., & Lu, Z. (2008) · Critical Care · doi:10.1186/cc6887 · Cited by 463 · see citing works
CDC Grand Rounds: Reducing Severe Traumatic Brain Injury in the United States
Wright, D. W., Kellermann, A. L., McGuire, L., Chen, B., & Popović, T. (2013) · PubMed Central · Cited by 136 · see citing works
Self-citationProgesterone's role in neuroprotection, a review of the evidence
Deutsch, E. R., Espinoza, T. R., Atif, F., Woodall, E., Kaylor, J., & Wright, D. W. (2013) · Brain Research · doi:10.1016/j.brainres.2013.07.014 · Cited by 110 · see citing works
Self-citationProgesterone in the clinical treatment of acute traumatic brain injury
Stein, D. G., & Wright, D. W. (2010) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2010.489549 · Cited by 108 · see citing works
Self-citationCDC grand rounds: reducing severe traumatic brain injury in the United States.
(2013) · PubMed · Cited by 89 · see citing works
Ducharme, N. A., Banks, W. A., Morley, J. E., Robinson, S. M., Niehoff, M. L., & Mattern, C. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.05.033 · Cited by 46 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [9]Jennett B Bond M Assessment of out come after severe brain damage. Lancet 1975 1 480 4 46957
Cited by
Sorted by citations
The far-reaching scope of neuroinflammation after traumatic brain injury
Simon, D. W., McGeachy, M. J., Bayır, H., Clark, R. S. B., Loane, D. J., & Kochanek, P. M. (2017) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.13 · Cited by 1,190 · see citing works
Sex Differences in Traumatic Brain Injury: What We Know and What We Should Know
Gupte, R. P., Brooks, W. M., Vukas, R. R., Pierce, J. D., & Harris, J. L. (2019) · Journal of Neurotrauma · doi:10.1089/neu.2018.6171 · Cited by 533 · see citing works
A Clinical Trial of Progesterone for Severe Traumatic Brain Injury
Skolnick, B. E., Maas, A. I., Narayan, R. K., van der Hoop, R. G., MacAllister, T., Ward, J. D., Nelson, N. R., & Stocchetti, N. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1411090 · Cited by 505 · see citing works
Hormonal Treatments for Major Depressive Disorder: State of the Art
Dwyer, J. B., Aftab, A., Radhakrishnan, R., Widge, A., Rodriguez, C. I., Carpenter, L. L., Nemeroff, C. B., McDonald, W. M., Kalin, N. H., & APA Council of Research Task Force on Novel Biomarkers and Treatments (2020) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2020.19080848 · Cited by 252 · see citing works
Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials
Stein, D. G. (2015) · Brain Injury · doi:10.3109/02699052.2015.1065344 · Cited by 249 · see citing works
Neuroprotective strategies for retinal disease
Pardue, M. T., & Allen, R. S. (2018) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2018.02.002 · Cited by 237 · see citing works
Sex-related responses after traumatic brain injury: Considerations for preclinical modeling
Späni, C. B., Braun, D. J., & Van Eldik, L. J. (2018) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2018.03.006 · Cited by 195 · see citing works
Gruenbaum, S. E., Zlotnik, A., Gruenbaum, B. F., Hersey, D., & Bilotta, F. (2016) · CNS Drugs · doi:10.1007/s40263-016-0355-2 · Cited by 86 · see citing works
“…1 and 3 months; ShortForm Health Survey scale at 3 and 6 months Progesterone treatment has no effect on clinical outcome in patients with moderate TBI Wright et al. 2014 [63] Randomized controlled trial 882 Progesterone Extended GOS at 6 months, mortality rate, Disability Rating Scale…”
BackgroundInfluentialRealising the therapeutic potential of neuroactive steroid modulators of the GABAA receptor
Belelli, D., Hogenkamp, D., Gee, K. W., & Lambert, J. J. (2020) · Neurobiology of Stress · doi:10.1016/j.ynstr.2019.100207 · Cited by 67 · see citing works
- Authors
- Wright, D. W., Yeatts, S. D., Silbergleit, R., Palesch, Y. Y., Hertzberg, V. S., Frankel, M., Goldstein, F. C., Caveney, A. F., Howlett-Smith, H., Bengelink, E. M., Manley, G. T., Merck, L. H., Janis, L. S., & Barsan, W. G.
- Affiliations
- Grady Memorial Hospital (US)
- Medical University of South Carolina (US)
- Emory University (US)
- University of Michigan (US)
- University of California, San Francisco (US)
- Brown University (US)
- National Institutes of Health (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2014-12-25
- Volume
- 371
- Issue
- 26
- Pages
- 2457-2466
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4303469
- OpenAlex
- W2166531273
- Cited by
- 567
- References
- 18
- Citations by year
- 2026: 36 · 2025: 33 · 2024: 36 · 2023: 25 · 2022: 38 · 2021: 39 · 2020: 50 · 2019: 61 · 2018: 53 · 2017: 60 · 2016: 75 · 2015: 57 · 2014: 2
- FWCI
- 41.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Emory University (UL1TR000454)
- National Institutes of Health (UL1TR001425, UL1TR000454)
- National Institute of Neurological Disorders and Stroke (U10NS058940, U10NS080369, U10NS059032, NS062778, U10NS059012, U01NS062778, U01NS056975, U10NS080377, U10NS058960, U10NS058927, U01NS059041)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Emergency Medicine › Trauma and Emergency Care Studies
- Keywords
- traumatic brain injury, progesterone, neuroprotection, early treatment, futility, phlebitis, thrombophlebitis, Glasgow Outcome Scale, disability outcome, mortality
- MeSH terms
- Accidents, Traffic, Adolescent, Adult, Aged, Aged, 80 and over, Brain Injuries, Double-Blind Method, Drug Administration Schedule, Female, Humans, Infusions, Intravenous, Male, Middle Aged, Phlebitis, Progesterone, Injury Severity Score, Treatment Failure, Glasgow Outcome Scale, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
