A Clinical Trial of Progesterone for Severe Trauma

7/18/2019 A Clinical Trial of Progesterone for Severe Trauma

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The New England Journal of Medicine

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#op!righ" $ 201% Maachue"" Medical &ocie"!. 'll righ" reer(ed.

T he n e w e n g l a n d j o u r n a l o f m e d i cin e

or iginal ar "icle

' #linical Trial of )roge"erone for &e(ereTrauma"ic *rain +njur!

*re"" E. &olnic, )h.D., 'ndrew +. Maa, M.D., )h.D., -aj . Nara!an, M.D.,

-oland /erri"en (an der oop, M.D., )h.D., Thoma Mac'lli"er, )h.D.,

John D. ard, M.D., Ne"a -. Nelon, M.).., and Nino &"ocche""i, M.D., for

"he &N')&E Trial +n(e"iga"or3

' * & T - '# T

BACKGR OUND

)roge"erone ha 4een aocia"ed wi"h ro4u" poi"i(e effec" in animal model of

"rauma"ic 4rain injur! 5T*+6 and wi"h clinical 4enef i" in "wo phae 2

r andomi7ed, con"rolled "rial. e in(e"iga"ed "he eff icac! and afe"! of proge"erone in a lar ge, pr opec"i(e, phae 8 randomi7ed clinical "r ial.

METHODS

e conduc"ed a mul"ina"ional place4o9con"rolled "rial, in which 11:5 pa"ien", 1;"o

<0 !ear of age, wi"h e(ere T*+ /lagow #oma &cale core, => ?on a cale of 8 "o

15, wi"h lower core indica"ing a reduced le(el of concioune@ and a" lea" one

reac9 "i(e pupil6 were r andoml! aigned "o recei(e proge"erone or place4o.

Doing 4e9 gan wi"hin > hour af"er injur! and con"inued for 120 hour. The

pr imar ! eff icac! end poin" wa "he /lagow Au"come &cale core a" ; mon"h

af"er "he in jur !.

RESULTS

)ropor"ional9odd anal!i wi"h co(ar ia"e adju"men" howed no "rea"men" effec"

of proge"erone a compared wi"h place4o odd ra"io, 0.:;B conf idence in"er (al,0.<< "o 1.1>6. The propor"ion of pa"ien" wi"h a f a(or a 4le ou"come on "he

/lagow Au"come &cale good reco(er! or modera"e dia 4ili"!6 wa 50.%C wi"h

pr oge"er 9 one, a compared wi"h 50.5C wi"h place4o. Mor"ali"! wa imilar in "he

"wo gr ou p. No r ele(an" afe"! difference were no"ed 4e"ween proge"erone and

place 4o.

CONCLUSIONS

)r imar ! and econdar ! eff icac! anal!e howed no clinical 4enef i" of pr oge"er one in pa"ien" wi"h e(ere T*+. Thee da"a "and in con"ra" "o "he

ro4u" pr eclinical da"a and reul" of earl! ingle9cen"er "rial "ha" pr o(ided "he

impe"u "o ini"ia"e phae 8 "rial. Funded 4! *- )harmaB &2 N')&E

#linicalTr ial.go( num4er , N#T011%80;%.6

From "he Depar "men" of

Neurour ger !, #uhing Neurocience

+n"i"u"e, of "r a Nor"h &hor e +J&chool of Medicine, Manhae", N

*.E.&., -..N.6B "he De9 par"men" of

Neurour ger !, ni(er i"! opi"al

'n"werp and ni(er i"! of 'n"9 wer p,

Edegem, *elgium '.+.M.6B *-

)harma, erndon -./.., T.M.,

N.-.N.6, and "he Depar"men" of

Neurour ger !, Girginia #ommonweal"h

ni(er i"!, -ich9 mond J.D..6 H

4o"h in GirginiaB and "he Depar"men"

of )h!io pa"holog! and Tranplan"a"ion,

Milan ni(er i"! and Neur o +n"eni(e

#are Fonda7ione +"i"u9 "o di -ico(ero e

#ura a #ara""ere &cien"i9 fico, #I /randa

Apedale Maggior e )oli9 clinico, Milan

N.&.6. 'ddr e reprin" reue" "oDr. &olnic a" Depar"men" of

Neur ourger !, Nor"h &hor e ni(er i"!opi"al, 800 #ommuni"! Dr., : Tower,

Manhae", N 11080, or a" 4olnic2K

nh.edu.

3' comple"e li" of in(e"iga"or in

"he &"ud! of a Neuropro"ec"i(e 'gen",)r o9 ge"erone, in &e(ere Trauma"ic

*rain +n jur ! &2 N')&E6 i pro(ided

in "he &upplemen"ar ! ' ppendiL,

a(aila4le a" NEJM.org.

Thi ar"icle wa pu4lihed on Decem4er 10,

201%, a" NEJM.org.

N Engl J Med 2014;37124!7"

7!# DOI

10#10$!% NEJM&'14110(0

Copyright © 2014 Massachusetts Medical

Society.



The New England Journal of Medicine

Downloaded from nejm.org on March 15, 2015. For peronal ue onl!. No o"her ue wi"hou" permiion.

#op!righ" $ 201% Maachue"" Medical &ocie"!. 'll righ" reer(ed.

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T


r auma"ic 4r ain in jur ! 5T*+6 i a

ma9 jor caue of dea"h and dia 4ili"!, wi"h

lar ge direc" and indirec" co" "o ocie"!.+n "he

ni"ed &"a"e, more "han 1.< million peron

ha(e a T*+ annuall!,1 and "he annual 4urden of

T*+ ha 4een e"ima"ed a" more "han <; 4illion.2

/lo 4all!, "he incidence of T*+ i increaing, par"icular l! in de(eloping coun"rie.8 'l"hough

in recen" !ear "here ha 4een a heigh"ened

in"ere" in mild T*+ and concuion, "he

pro4lem of more e(ere T*+ remain u4"an"ial,

depi"e im pr o(emen" in "r au9 ma !"em andcri"ical care. Mor"ali"! ra"e of a ppr oLima"el!

%0C ha(e 4een repor"ed in a r e(iew of unelec"ed

o4er (a"ional "udie.%

T*+ i a pr ogr ei(e diorder, in which "he

pr i9 mar ! injur! ini"ia"e a compleL euence of 4io9 chemical and me"a4olic change "ha" lead

"o pr ogr ei(e "iue damage and cell dea"h.Thee econdar ! e(en" offer oppor"uni"ie for

"her a peu9 "ic in"er (en"ion. Mul"iple

pa"ho ph!iological mech9 anim are ac"i(e in

"hi compleL diorder, wi"h con"uion, diffue

aLonal in jur !, hemor rhage, and !"emic

inul" occurring "o (ar!ing de9 gree.5,;

)o"en"ial "herapeu"ic agen" ma! need "o

"arge" mul"iple mechanim in or der "o 4e

clinicall! effec"i(e.)roge"erone ha 4een hown "o ha(e 4r oad

neur o pr o"ec"i(e proper"ie in mul"iple animal

pecie and in a (arie"! of model of neur ologic

in jur !. Mul"ifac"orial effec" of proge"erone in9

clude inhi4i"ion of inf lamma"or ! c!"o ine,re9 duced le(el of inf lamma"ion9rela"ed fac"or,

pr e9 (en"ion of eLci"o"oLici"!, reduc"ion of

a po p"oi, and con"rol of (aogenic edema.<910

The pr oge"er 9 one recep"or pla! a e! role in

"hee neuropro"ec9 "i(e effec".11 ' "o"al of 20r eear ch group wor9 ing wi"h four pecie and

22 diff er en" model ha(e found neur o pr o"ec"i(e

effec" of proge"erone in more "han 1>0

eLperimen"al pharmacologic "udie.12

+naddi"ion, "wo phae 2 randomi7ed, con"r olled

clinical "rial wi"h proge"erone howed a

clinical 4enef i".18,1% An "he 4ai of "hee

collec"i(e da"a, "wo phae 8 "rial were

ini"ia"ed a" around "he ame "ime "he &"ud! of a

Neur o pr o"ec"i(e 'gen", )roge"erone, in &e(er e

Trauma"ic *rain +njur! 5&2 N')&E6 and "he )ro9

ge"erone for "he Trea"men" of Trauma"ic *rain

+njur! 5)-ATE#T +++6 "r ial.15

&2 N')&E, a "rial ponored 4! *-

)har ma, wa deigned "o in(e"iga"e "he clinical

eff ec"i(e9 ne of proge"erone, pr o(ided in a

;C o! 4ean9 oil emulion a ar ead!9"o9ue formula"ion, under



well9con"rolled condi"ion. The )-ATE#T +++ "r ial, funded 4! "he

Na"ional +n"i"u"e of eal"h, wa conduc"ed in parallel, 4u" "he

"ud! wa hal"ed on "he 4ai of a fu"ili"! anal!i performed

af"er >>2 pa"ien" had undergone randomi7a"ion. ere, we repor"

"he reul" of "he comple"ed &2 N')&E "r ial.

M E T A D&

STUD) DESIGN

e conduc"ed a mul"ina"ional, pr opec"i(e, dou9 4le94lind, parallel9group "rial in which pa"ien" wi"h e(ere T*+ were

r andoml! aigned "o in"r a9 (enou proge"erone or place4o.

- andomi7a"ion wa performed from Jul! 2010 "hrough

&e p"em 4er

2018. )a"ien" were recrui"ed a" le(el 1 or eJui(a9 len" "rauma

cen"er in 21 coun"rie. The "rial pr o9 "ocol 5a(aila4le wi"h "he

full "eL" of "hi ar"icle a" NEJM.or g6 wa a ppr o(ed 4! r egula"or !

au"hor i9 "ie in each coun"r ! and 4! "he local or r egional e"hic

commi""ee for each par"icipa"ing cen"er . Thi repor" i

coni"en" wi"h "he "ud! deign and procedure preen"ed in

"he pr o"ocol.

ELIGIBILIT)

' "o"al of 10,51: male and female pa"ien", 1; "o

<0 !ear of age, wi"h e(ere nonpene"ra"ing T*+ were creened

for eligi4ili"! a" admiion "o "he "ud! hopi"al. Eligi4ili"!

cri"eria included a /lagow #oma &cale /#&6

core, aeed af "er reuci"a"ion, of > or le

on a cale from 8 "o 15, wi"h lower core

indica"ing a reduced le(el of concioune6, a

Marhall claif ica"ion cor e1; of ++ or higher

on a cale from + "o G+, wi"h a core O++

indica"ing (ii4le pa"hologic change or wore,

a aeed on "he 4ai of compu"ed "o9

mogr a ph! ?#T@6, a" lea" one reac"i(e pupil,

a 4od! weigh" of %5 "o 185 g, ini"ia"ion of

"r ea"men" wi"hin > hour af"er in jur !, and a

clinical indica9 "ion for moni"oring "he

in"racranial pr eur e.)a"ien" were eLcluded if "he! had a /#&

cor e of 8 and 4ila"er all! f iLed and dila"ed

pupil, a life eLpec"anc! of le "han 2% hour,

pr olonged or uncorrec"a4le h! poLemia par"ial

preure of ar"erial oL!gen, P;0 mm g6,h! po"enion 5!9 "olic 4lood preure, P:0 mm

g6 a" "he "ime of randomi7a"ion, pinal cordin jur !, pr egnanc!, onl! an iola"ed epidural

hema"oma, or coma "ha" wa upec"ed "o 4e

due pr imar il! "o o"her caue. ' comple"e li"

of incluion and eLclu9 ion cri"eria i pr o(ided

in "he &u pplemen"ar ! 'ppendiL, a(aila4le a"

NEJM.or g.

2%;> n engl j med 8<1B2; nejm.org decem4er 25, 201%



)r oge "er one for &e ( er e Tr aum a"ic *r a in +n jur !

*ecaue all "he po"en"ial par"icipan" were

unconciou a" "he "ime of "ud! en"r !, wr i""en

informed conen" wa o4"ained from a legall!

accep"a4le r e pr een"a"i(e 4efore r andomi7a"ion,according "o na"ional regula"ion and e"hic9com9

mi""ee reuiremen". +n ome coun"rie, conen"

for par"icipa"ion wa allowed "o 4e pr o(ided

4! an independen" ph!ician.

STUD) *ROCEDURES AND TREATMENTS

-andomi7a"ion wa implemen"ed wi"h "he ue

of an in"er ac"i(e e494aed repone !"em, wi"h a 4loc deign of four "r a"if ied according

"o geo9 graphic region 'ia, Europe, Nor"h

'merica, and &ou"h 'merica6. )a"ien" were

r andoml! aigned

in a 11 ra"io "o recei(e proge"erone or place 4o./eneral "rea"men" and "he "rea"men" of r aied

in"racranial preure were in accordance wi"h pu4lihed in"erna"ional guideline.1<

The "ud! drug proge"erone and place 4o6

were pr o(ided in 2509ml 4o""le wi"h iden"ical

appearance, con"aining a lipid emulion coni"9

ing of ;C o! 4ean oil and 1.2C egg leci"hin

phopholipid, wi"h "he addi"ion of 2.0 mg of

pr o9 ge"erone per millili"er for "he ac"i(e

"r ea"men" *-9100, Freeniu a4i6. Drug

infuion wa "ar"ed in"r a(enoul! wi"h a

loading doe of

0.<1 mg per ilogram of 4od! weigh" per hour

for 1 hour, followed 4! 0.50 mg per ilogram

per hour for 11: hour, "hrough a dedica"ed

per i pher al in"r a(enou ca"he"er or dedica"ed

lumen of a mul"i9 lumen cen"ral ca"he"er .During "he f ir" ; da!, ar"erial 4lood

gae, in"racranial preure, cere4ral perfuion

pr eur e, and "herapeu"ic in"eni"! le(el a

core of all "herapie ued "o con"rol ele(a"ed

in"r acr anial preure6 were recorded. &"andard

la 4or a"or ! a9 emen" were performed on

da! ; and 15, and a econd #T "ud! wa

cheduled "o 4e per f or med on da! ;. )a"ien"

were moni"ored for Qneur o9 worening,R a

defined 4! Morri e" al.,1> dail! "hrough da!

15 ee "he "ud! pro"ocol f or def ini9 "ion of

neuroworening6. #oncurr en" medica9 "ion,

urgerie, and ad(ere e(en" wer e record9 ed

for "he fir" 15 da!, and er iou ad(er e e(en"

were recorded "hroughou" "he dura"ion of "he

"ud!B pa"ien" wi"h uch e(en" were

followed un"il reolu"ion or for a" lea" ;

mon"h. Two follow9up (ii" were planned for

:0 S156 da! and 1>0 S806 da! af"er in jur !,

a" which "ime "he ou"come meaure were

aeed.#linical da"a were collec"ed "hrough an elec9



"ronic da"a9cap"ure !"em

wi"h 4uil"9in da"a chec. 'll

#T can were re(iewed and

cor ed 4! a cen"ral r eader .

OU

TC

O

ME

ME

AS

UR

ES

The pr imar ! ou"come meaure

wa "he /lagow Au"come

&cale 5/A&6 core a" ; mon"h

af"er "he in jur !. The /A& and

"he EL"ended /A& /A&9E6

were admini"ered wi"h "he

ue of a "r uc"ur ed in"er(iew

4! a "rained local "aff

mem4er and were cored 4!

"he in(e"iga"or according "o

"he "andardi7ed approach.1:

The /A& cap"ure in9

forma"ion on "he degree of

reco(er! in "erm of dia 4ili"!

and handicap due "o 4rain

injur! r a"her "han impairmen".

The cale ha f i(e le(el dea"h,(ege"a"i(e "a"e, e(ere

dia 4ili"!, modera"e di9

a 4ili"!, and good reco(er!B

dea"h and (ege"a"i(e "a"e were

collaped for "he anal!i in"hi "ud! 4ecaue "he! were

conidered "o 4e euall! unde9

ir a 4le.&econdar! ou"come meaure included "he

/A& core a" 8 mon"h, mor"ali"! a" 1

mon"h and ; mon"h, and "he /A&9E core. The

/A&9E differ from "he /A& in "ha" "he "hree

higher func"ional le(el 5e(ere dia 4ili"!,modera"e di9 a 4ili"!, and good reco(er!6 are

each u4di(ided in"o a lower and upper

ca"egor !. 'ddi" ional ec9 ondar ! ou"come

meaure included change in in"racranial

preure, cere4ral perfuion pr eur e, and"herapeu"ic in"eni"! le(el, along wi"h chang9 e

in in"racranial pa"hologic finding a aeed

on "he #T can o4"ained on da! ;. The 8;9+"em

&hor"9Form eal"h &ur(e! &F98;6 cale wa

ad9 mini"ered a" 8 and ; mon"h "o aeuali"! of life for "hoe pa"ien" a4le "o comple"e

"he cale.

STUD) O+ER SIGHT

'n independen" da"a and afe"! moni"oring

4oar d per iodicall! re(iewed 4linded da"a. &"aff

from )-' eal"h &cience and +N# -eearch

conduc"ed on9 i"e (ii" "o ae pro"ocol

compliance and ad9 herence "o /ood #linical

)rac"ice guideline and "o perform da"a

(er if ica"ion and uer! r eolu"ion. Medical

moni"or re(iewed elec"ed da"a cen"r al9 l!, and

r e pr een"a"i(e of "he ponor r egular l! (ii"ed

"he "ud! i"e "o moni"or "ud! com pli9 ance.

The "eering commi""ee ee "he &u pplemen9 "ar!

'ppendiL6 ai"ed "he ponor wi"h "ud!

deign, da"a in"erpre"a"ion, and "he de(elo pmen"

of "he manucrip". Da"a managemen" and "a"i9"ical anal!i wa performed 4! )-' eal"h

&ci9 ence. 'nal!7a4le da"ae" were pr o(ided

"o "he

n engl j med 8<1B2; nejm.org decem4er 25, 201% 2%;:




"eering commi""ee for a chec of anal!e

and fur"her eL plor a"or ! anal!e. The deciion "o

u49 mi" "he manucrip" for pu4lica"ion wa

made 4! "he "eering commi""ee and wa

a ppr o(ed 4! "he ponor. The mem4er of "he

"eering commi""ee (ouch for "he in"egr i"! of "he

da"a and anal!e.

STATISTICAL ANAL)SIS

e e"ima"ed "ha" a ample of 11>0 pa"ien",

wi"h a 11 randomi7a"ion ra"io, would 4e

reuired f or "he "ud! "o de"ec" an odd ra"io of

1.50, indica"9 ing an im pr o(emen" in ou"come10C effec" i7e6 a" "he 1C ignif icance le(el

"wo9ided6. The am9 ple9i7e e"ima"ion wa

4aed on "he ue of a pr o9 por"ional9odd

model20 "o anal!7e "he pr imar ! ou"9 come(aria4le 5/A& core a" ; mon"h af"er in jur !6.

The anal!e were performed on da"a from

"he modified in"en"ion9"o9"rea" popula"ion,which eL9 cluded 1; pa"ien" who ne(er recei(ed

"he "ud! drug. Thi approach wa agreed "o 4!

"he Food and Drug 'dmini"ra"ion. +n "he

pr o por"ional9 odd anal!i, co(ar ia"e

adju"men" wa per f or med for geographic region

'ia, Europe, Nor"h 'mer9 ica, and &ou"h

'merica6 and "he 4aeline (alue of age, /#&

mo"or core core of 1 or 2 (. 8 (.% (. 5 or ;, on a cale from 1 "o ;, wi"h lower

core indica"ing a lower le(el of

concioune6, pu pillar ! repone 4ila"eral

repone (. unila"9 eral repone, no reac"i(e

pupil, or no" "e"a 4le6, and Marhall claif

ica"ion + or ++ (. +++ (. +G (. G or G+6.' a econdar ! e(alua"ion, eff icac! wa

ana9 l!7ed wi"h "he ue of a liding dicho"om!21

of "he /A& ou"come a" ; mon"h. *aeline

pr ogno"ic ri wa calcula"ed 4! mean of "he

model de(el9 oped 4! u elho(en e" al.,22 and

pa"ien" wer e "hen raned according "o

progno"ic ri and ca"egori7ed in"o "hree

group on "he 4ai of "he prognoi wor",in"ermedia"e, and 4e"6. The lid9 ing dicho"om!

pr o(ide a mean "o ae each of "he "hree

progno"ic group indi(iduall! in9 "ead of "he

en"ire group, increaing "he eni"i(9 i"! of "he

anal!i. The anal!i ued a #ochr an Man"el

aen7el chi9uare "e" wi"h ad ju"men" for

geographic r egion.

- E & T &

STUD) *AR TICI*ANTS AND DR UG LE+ELS

)a"ien" were recrui"ed from Jul! 2010 "hr ough

&ep"em4er 2018, wi"h "he f inal ;9mon"h (ii"

oc9 curring 4! "he end of March

201%. ' "o"al of 11:5



pa"ien" underwen" randomi7a"ion, wi"h in"r a(e9 nou

admini"ra"ion of proge"erone ini"ia"ed in

5:1 pa"ien" and place4o admini"ered in 5>> pa9 "ien" "he

modified in"en"ion9"o9"rea" popula"ion6B

1; pa"ien" were eLcluded 4ecaue "he! did no" recei(e "he

aigned "ud! drug. Af "he 11<: pa9 "ien" in "he modif ied

in"en"ion9"o9"rea" po pula9 "ion, :;.0C were followed for ;

mon"h or died 4efore ; mon"h Fig. 16. There were no

meaning9 ful pro"ocol (iola"ion. 'f"er cen"rali7ed ae9 men"

of #T can, le "han 1C of "he pa"ien" who had undergone

randomi7a"ion were in Mar9 hall claif ica"ion + i.e., no

r adiologicall! ig9 nif ican" a 4normali"! on 4aeline #T6.

*aeline charac"eri"ic, including /#& o(er 9 all core and

mo"or core, Marhall claif ica"ion, and pu pillar ! reac"i(i"!,

were imilar in "he "wo group Ta4le 16. Drug9le(el aemen"

wa per 9 formed 2 da! af"er "he ini"ial doing. )r oge"er 9 one

"rea"men" reul"ed in a median pr oge"er one le(el of 888.5 ng per

millili"er in"eruar"ile r ange,2;>.: "o %05.<B 10;1 nmol per li"er ?in"er Juar "ile range, >55 "o

12:0@6B "hi (alue wa imilar "o "he mean le(el o4"ained in "he

phae 2 )- ATE#T "rial 8%< ng per millili"er ?1108 nmol per

li"er@6, which pr o(ided "he earl! uppor" for "he curr en" "rial.

Drug le(el in "he cere4ropinal f luid were no" moni"or ed.

CLINICAL OUTCOMES

The pr imar ! end poin", "he /A& core a" ;

mon"h, did no" differ ignif ican"l! 4e"ween "he

pr oge"er 9 one group and "he place4o group

Ta4le 26. The propor"ional9odd model re(ealed

no effec" of proge"erone "rea"men" in ei"her

unadju"ed or ad9 ju"ed anal!e adju"ed

odd ra"io, 0.:;B :5C confidence in"er (al ?#+@,

0.<< "o 1.1>6. The pr o por 9 "ion of pa"ien" wi"h

an o(erall f a(or a 4le ou"come good reco(er! or

modera"e dia 4ili"!6 on "he /A& wa 50.%C in

"he proge"erone group and 50.5C in "he

place4o group. The propor"ion of pa"ien" who

were in a (ege"a"i(e "a"e or who died wa alo

imilar in "he "wo group 22.2C in "he pr o9

ge"erone group and 22.8C in "he place4o gr ou p

Ta4le &1 in "he &u pplemen"ar ! 'ppendiL6. The

/A&9E alo did no" re(eal ignifican" diff er ence

4e"ween "he "wo "ud! group a" 8 or ; mon"h.

SECONDAR ) OUTCOMES

The liding dicho"om!, which rela"e ou"come

"o 4aeline progno"ic ri, re(ealed no ignif

ican" difference 4e"ween proge"erone

"rea"men" and

2%<0 n engl j med 8<1B2; nejm.org decem4er 25, 201%




10,51: )a"ien" were aeed for eligi4ili"!

:82% ere eLcluded>8%5 Did no" mee" eligi4ili"! cri"eria

180 ad '- who declined conen"5%1 Did no" ha(e '- a(aila4le

80> ad o"her reaon

11:5 nderwen" randomi7a"ion

5:< ere aigned "o recei(e proge"erone5:1 -ecei(ed proge"erone

; Did no" recei(e proge"eroneeligi4ili"! ree(alua"ed, pa"ien"died, or admini"ra"i(e reaon6

5:> ere aigned "o recei(e place4o5>> -ecei(ed place4o

10 Did no" recei(e place4o 5eligi4ili"!

ree(alua"ed, pa"ien" died, conen"wi"hdrawn, or admini"ra"i(e reaon6

1< ere lo" "o follow9up af"er "rea"men"10: Died included in anal!i6

< Dicon"inued in"er(en"ion owing "owi"hdrawn conen"

1% ere lo" "o follow9up af"er "rea"men":5 Died included in anal!i6

% Dicon"inued in"er(en"ion owing "owi"hdrawn conen"

% Dicon"inued in"er(en"ion owing "oin(e"iga"or deciion

1 ad ad(ere e(en"

5:1 ere included in modified in"en"ion9"o9"rea" anal!i

25 included wi"h impu"ed ;9mo /A& core

5>> ere included in modified in"en"ion9"o9"rea" anal!i

2% included wi"h impu"ed ;9mo /A& core

,-g./e 1# S.d En/&llen R'nd&-'-&n 'nd ,&ll&5".6 & 8e *'-en9#The modified in"en"ion9"o9"r ea" popula"ion eLcluded 1; pa"ien" ; pa"ien" in "he proge"erone group and 10 in "he

place4o group6 4ecaue "he! did no" recei(e an! "ud! dr ug. ' "o"al of 81 pa"ien" 1< pa"ien" in "he proge"erone

group and 1% in "he place4o group6 were lo" "o follow9up. ' "o"al of 20% pa"ien" 10: pa"ien" in "he proge"erone

gr oup and :5 in "he place4o group6 died 4efore ; mon"h of follow9up. Da"a on 11<: pa"ien" were included in "he

efficac! anal!i. Miing (alue were fir" impu"ed 4! carr !ing forward "he /lagow Au"come &cale /A&6 ae9

men" a" mon"h 8. +f a par"icipan" did no" ha(e a /A& core a" 8 or ; mon"h, "he miing (alue wa impu"ed wi"h

"he ue of "he pr o por "ional9odd model. '- deno"e legall! accep"a4le r e pr een"a"i(e.

place4o Fig. 26. Thi approach howed no indi9

ca"ion of eff icac! in "he group 4aed on pr og9

noi wor", in"ermedia"e, and 4e"6 Ta4le &2in "he &u pplemen"ar ! 'ppendiL how reul"

of anal!e of 4aeline progno"ic fac"or6. The

u4group anal!e according "o Marhall cla9

if ica"ion, decom pr ei(e cr aniec"om! !e

(. no6, an! o"her ur ger ! 5!e (. no6, andiola"ed head injur! (er u mul"iple "rauma

howed no ignif ican" odd ra"io Ta4le 26.

#ere4ral per 9 fuion preure and "herapeu"ic

in"eni"! le(el did no" differ ignif ican"l!

4e"ween "he pr oge9

"erone group and "he place4o group Ta4le &8

and &% in "he &u pplemen"ar ! 'ppendiL6. Da"a

on "he &F98;, which were a(aila4le for a "o"al of <28 pa"ien" a" ; mon"h <%.2C of ur (i(or6,re9 (ealed no ignif ican" difference in

ph!ical or men"al compoi"e ummar ! cor e.

AD+ER SE E+ENTS

The di"ri4u"ion of ad(ere e(en" i hown in

Ta4le 8. There were no ignif ican" difference

in "he ra"e of ad(ere e(en" 4e"ween

pr oge"er one "rea"men" and place 4o.



n engl j med 8<1B2; nejm.org decem4er 25, 201% 2%<1




D + & # & & +AN

Aur reul" do no" uppor" "he h! po"hei7ed u9

per ior i"! of proge"erone "rea"men" o(er

place 4o in pa"ien" wi"h e(ere T*+, a aeed

4! mean of "he /A& or mor"ali"!. T*+ i a

compleL, he"9 erogeneou diorder, in which "he

pr imar ! in jur ! ini"ia"e a (arie"! of econdar !injur! cacade.

Thee cacade in(ol(e (ar iou procee "ha"ma! no" 4e r eponi(e "o mono"her a p!, a ha 4een hown 4! "he failure of pre(ioul! "udiedmono9 "herapie "ha" ha(e "arge"ed ingle

recep"or or pecific mechanim,28,2% depi"econider a 4le up9 por"i(e eLperimen"al da"a.&!"emic and eL"ra9 neuronal effec" of "rauma

alo r eJuir e conider9 a"ion wi"h repec" "o

"heir effec" on mor"ali"!

T':le 1# B'9el-ne C8'/';e/-9-;9 & 8e M&d--ed Inen-&n"&"T/e' *&6.l'-&n#<

*/&ge9e/&ne *l';e:&C8'/';e/-9-; =N > $(1? =N > $@@?

'ge H !r

Median 85 8%

+n"eruar"ile range 2851 2%50

Male eL H no. C6 %;% <>.56 %;8 <>.<6

/eographic regionT

'ia ;2 10.56 5> :.:6

Europe 2<: %<.26 2<< %<.16

Nor"h 'merica 21: 8<.16 220 8<.%6

&ou"h 'merica 81 5.26 88 5.;6

#aue of injur! H no. C6

Mo"or (ehicle or mo"orc!cle acciden" 8;: ;2.%6 8;% ;1.:6

Fall 12% 21.06 1%2 2%.16

&por" or recrea"ion acciden" or o"her e(en" :> 1;.;6 >2 18.:6

/lagow #oma &cale core H no. C6U

A(erall core

8 52 >.>6 ;% 10.:6

%; 2;2 %%.86 2<; %;.:6

< or > 2<; %;.<6 2%> %2.26

Da"a miing 1 0.26 0

Mo"or core

18 218 8;.06 2%1 %1.06

%; 8<; ;8.;6 8%5 5>.<6

Da"a miing 2 0.86 2 0.86

)upillar! repone H no. C6

*o"h reac"ing %>0 >1.26 %<5 >0.>6

Ane reac"ing 10: 1>.%6 10< 1>.26

A"her or un"e"a4le 2 0.86 ; 1.06

Marhall claifica"ion H no. C6V

+ ; 1.06 % 0.<6

++ 285 8:.>6 288 8:.;6

+++ or +G 218 8;.06 1:: 88.>6

G or G+ 18% 22.<6 151 25.<6

Da"a miing 8 0.56 1 0.26



2%<2 n engl j med 8<1B2; nejm.org decem4er 25, 201%




T':le 1# =C&n-n.ed#?

*/&ge9e/&ne *l';e:&C8'/';e/-9-; =N > $(1? =N > $@@?

Trauma"ic u4arachnoid hemorrhage H no. C6W %%: <;.06 %5; <<.;6

#onfirmed or upec"ed h!poLemia H no. C6‖ 52 >.>6 %5 <.<6

#onfirmed or upec"ed h!po"enion H no. C633 :8 15.<6 <> 18.86

Time from injur! "o fir" doe

Median < hr % min < hr 2 min

+n"eruar"ile range ; hr 0 min "o < hr %5 min 5 hr 58 min "o < hr %5 min

3 There were no ignifican" 4e"ween9group difference a" 4aeline. /eographic region were defined a follow 'ia included #hina, Mala!ia, &ingapore, Taiwan, and ThailandB Europe

included 'u"ria, *elgium, "he #7ech -epu4lic, Finland, France, /erman!, ungar!, +rael, +"al!, "he Ne"herland, and-omaniaB Nor"h 'merica included "he ni"ed &"a"eB and &ou"h 'merica included 'rgen"ina.

U A(erall core on "he /lagow #oma &cale range from 8 "o 15, wi"h lower core indica"ing a reduced le(el ofcon9 cioune. Mo"or core range from 1 "o ;, wi"h lower core indica"ing a reduced mo"or repone.

V The Marhall claifica"ion i 4aed on a re(iew of #T can, wi"h a core of + indica"ing normal finding, ++indica"ing diffue injur!, +++ or +G indica"ing radiologic ign of ele(a"ed in"racranial preure, and G or G+ indica"ing ama leion.

W Da"a were miing for % pa"ien" in "he proge"erone group and for 1 in "he place4o group. ‖ !poLemia wa defined a a par"ial preure of ar"erial oL!gen of le "han ;0 mm g. Da"a were miing for 1; pa9 "ien" in "he proge"erone group and for 22 in "he place4o group.

33 !po"enion a defined a a !"olic 4lood preure of le "han :0 mm g. Da"a were miing for 1% pa"ien" in "he proge"erone group and for 12 in "he place4o group.

among pa"ien" wi"h T*+.25 Thee compleL

in jur ! mechanim ugge" "ha" a ucceful

"her a peu9 "ic agen" hould inf luence e(eral

mechanim ra"her "han a ingle cacade.An "he 4ai of "he eLperimen"al da"a,

pr oge9 "erone would appear "o 4e an appropria"e

candi9 da"e for "hi pluripo"en"ial role, ha(ing

4een hown "o pr e(en" inf lamma"ion 4!inhi4i"ing "he produc"ion of inf lamma"or !

c!"o ine 5e.g., "umor necroi fac"or α6, a

well a 4! r educing le(el of inf lamma"ion9

rela"ed fac"or uch a complemen" fac"or #8

fragmen" and inhi4i"ing "he ac"i(a"ion of

microglial cell. +n addi"ion, proge"erone ha

4een hown "o pr e(en" eLci"o9 "oLici"! and

limi" apop"oi 4! pr e(en"ing 4io9 chemical

inul", uch a calcium #a2X6 f luL and ni"ric

oLide produc"ion, and 4! decreaing le(el of

capae 8. Finall!, proge"erone ha alo 4een

hown "o limi" (aogenic edema "hrough r econ9

"i"u"ion of "he 4lood4rain 4arrier and modula9

"ion of "he auaporin9% wa"er "r anpor "er .2;

)r eliminar ! clinical da"a o4"ained wi"h "he

ue of (ar iou proge"erone formula"ion and

rou"e of deli(er!, com4ined wi"h eL per imen"al

da"a howing adeua"e 4rain pene"ra"ion, pr o9

(ided ini"ial uppor" for a neur o pr o"ec"i(e role of

proge"erone in T*+. The ini"ial )-ATE#T

"r ial18 recrui"ed 100 pa"ien" from a ingle i"e

who had a /#& core of % "o 12. Trea"men"

wa ini"ia"ed

wi"hin 11 hour af"er in jur !, wi"h a <29hour

"rea"men" dura"ion, and wa aocia"ed wi"h a

reduc"ion in "he ra"e of dea"h from an! caue, a

compared wi"h place4o 18.0C (. 80.%CB

r ela9 "i(e ri, 0.%8B :5C #+, 0.1> "o 0.::6. '

imilar ingle9i"e "rial1% in #hina recrui"ed 15:

pa"ien" who had a /#& core of > or lower .)roge"erone "rea"men", which wa ini"ia"ed

wi"hin > hour af"er injur! 4! mean of

in"ramucular injec"ion, wi"h a 1209hour

"rea"men" dura"ion, wa aoci9 a"ed wi"h

reduced mor"ali"!, a compared wi"h place 4o

1>C (. 82C, ) Y 0.0%6. The "ime win9 dow

and dura"ion of "rea"men" in &2 N')&E were

4aed largel! on "hee "wo "udie.The long hi"or ! of failed T*+ "rial,

including "he curren" "rial, i pr o4a 4l! due "o

e(eral fac9 "or, including "he compleLi"! and(aria4ili"! of "he injur! and "he fac" "ha" mul"iple

direc" and indirec" injur! mechanim are a"

wor imul"a9 neoul!. There ma! alo 4e

ineni"i(i"! of "he a(aila4le ou"come meaure.

The lac of mecha9 ni"ic earl! end poin" and

"he a4ence of r eli9 a4le 4iomarer "o guide

clinical de(elo pmen" and inform clinical9"rial

deign ma! 4e conid9 ered "o 4e major o4"acle

"o "he de(elo pmen" of neur o pr o"ec"i(e agen"

for T*+. +n addi"ion, cur 9 ren" approache "o

"he charac"eri7a"ion of T*+ are mainl!

unidimenional 4aed on /#& cor e or

Marhall claif ica"ion6 and do no" per mi"






T':le 2# Re9.l9 & E-;'; An'l9-9 -n 8e M&d--ed Inen-&n"&"T/e' *&6.l'-&n#<

*/&ge9e/&ne *l';e:& Odd9 R'-&O.;&e =N > $(1? =N > $@@? =($ CI?

)rimar! efficac! anal!i H no. C6 0.:; 0.<<1.1>6

Dead or (ege"a"i(e "a"e 181 22.26 181 22.86

&e(ere dia4ili"! 1;2 2<.%6 1;0 2<.26

Modera"e dia4ili"! 10: 1>.%6 11% 1:.%6

/ood reco(er! 1>: 82.06 1>8 81.16

&u4group anal!e H no.U

/eographic region

'ia ;1 5; 1.85 0.;52.>06

Europe 2;< 2;5 0.>1 0.5>1.1%6

Nor"h 'merica 20> 210 1.8; 0.:82.006

&ou"h 'merica 80 82 0.%; 0.1<1.2<6

Marhall claifica"ion

+ or ++ 221 222 1.01 0.;:1.%:6

+++ or +G 205 1:2 0.:5 0.;%1.%16

G or G+ 180 1%5 0.:% 0.5>1.586

Decomprei(e craniec"om!

e 182 :< 0.>; 0.501.%>6

No %8% %;; 1.10 0.>%1.%26

&urger!

e %01 8<< 0.:8 0.<01.286

No 1<5 1>; 1.11 0.<81.;:6

+njur!

ead injur! alone << ;5 0.>1 0.%21.5<6

Mul"iple "rauma %>: %:> 1.0% 0.>11.886

Time "o fir" doe

=; hr 1%% 15< 1.81 0.>82.0<6

Z; hr %22 %0; 0.:2 0.<01.216

3 #+ deno"e confidence in"er(al. The primar! anal!i wa performed a a propor"ional9odd anal!i wi"h adju"men" for "he following 4aeline (ari9

a4le geographic region, age, /lagow #oma &cale mo"or core, pupillar! repone, and Marhall claifica"ion. Theunadju"ed anal!i !ielded imilar reul" odd ra"io, 0.:>B :5C #+ 0.<: "o 1.216.

U &u4group anal!e were re"ric"ed "o pa"ien" wi"h comple"e ou"come da"a a" ; mon"h, and "rea"men" effec" werean9 al!7ed according "o "he dicho"omi7ed /lagow Au"come &cale fa(ora4le (. unfa(ora4le6. 'n odd ra"io of more"han1.00 repreen" a 4enefi" of ac"i(e "rea"men"B "he reul" of "he unadju"ed anal!i are preen"ed.

a ppr o pr ia"el! "arge"ed "her a p!.Mul"idimenion9 al approache are needed for

4e""er char ac"er i7a9 "ion of T*+ in order "o

facili"a"e indi(iduali7ed "r ea"men".2<

imi"a"ion in "he a4ili"! "o "ranla"e eLperi9

men"al da"a "o "he con"eL" of T*+ in human

ma! alo ha(e con"ri4u"ed "o "he "rial failure. '

more !"ema"ic approach appear "o 4e nece9

ar! "o ad(ance "herapeu"ic in T*+. The

4aic

cience conor"ium approach curr en"l! under wa!, a a par" of "he #om4a" #aual"! #are

- eear ch )rogram en"i"led Apera"ion *rain

Trauma Ther 9 ap! #onor"ium, ma! 4e one

im pr o(emen" in dr ug9 candida"e elec"ion.2>

+n concluion, our da"a indica"e "ha" pr oge9

"erone, a admini"ered in "hi "rial, had no

clinical 4enefi" in "he "rea"men" of e(ere T*+.

The nega"i(e reul" of "hi "ud!, com4ined wi"h

"he reul" of



2%<% n engl j med 8<1B2; nejm.org decem4er 25, 201%




O.;&e&/9 */&gn&9-9

=N>3(3?Ine/ed-'e */&gn&9-9

=N>3(4?Be9 */&gn&9-9

=N> 3(2?

)roge"erone

NY 1>56)lace4o

NY 20>6

)roge"erone

NY 20;6

)lace4o

NY 1>>6

)roge"erone

NY 2006

)lace4o

NY 1: 2 6

Dea"h

Gege"a"i(e "a"e

&e(ere dia4ili"!

nfa(ora4le

;% 8%.;C6

nfa(ora4le

>1 8>.:C6 nfa(ora4le110 58.%C6

nfa(ora4le108 5%.>C6

nfa(ora4le108 51.5C6

nfa(ora4le:0 %;.:C6

Modera"e dia4ili"!

/ood reco(er!

Fa(ora4le121 ;5.%C6

Fa(ora4le12< ;1.1C6

Fa(ora4le:; %;.;C6

Fa(ora4le>5 %5.2C6

Fa(ora4le:< %>.5C6

Fa(ora4le102 58.1C6

)Y 0.8; )Y 0.>2 )Y 0.8>

,-g./e 2# E77 -;'; An'l9-9 5-8 8e U9e & ' Sl-d-ng D-;8&& A66/&';8#

+n "he liding dicho"om! approach, "he /A& wa dicho"omi7ed for anal!i, 4u" "he pli" for dicho"om! wa differ9

en"ia"ed according "o "he 4aeline progno"ic ri. )rogno"ic gr oup 4aed on wor", in"ermedia"e, and 4e" pr og9noi622 were defined 4! 4aeline pr ogno"ic fac"or "ha" included age, /lagow #oma &cale mo"or core 1 or 2 (.

8 (. % (. 5 or ;B core range from 1 "o ;, wi"h lower core indica"ing reduced mo"or repone6, pupillar ! re9

pone 4ila"eral repone (. unila"eral repone, no reac"i(e pupil, or no" "e"a4le6, preence or a4ence of h!9

poLemia, preence or a4ence of h! po"enion, Mar hall[ claifica"ion + or ++ (. +++ (. +G (. G or G+6, and pr e9

ence or a4ence of "rauma"ic u4arachnoid hemorrhage. The Marhall claifica"ion i 4aed on a re(iew of #T

canB core range from + "o G+, wi"h a core of ++ or higher indica"ing (ii4le pa"hologic change or wore. The

arrow indica"e "he pli" for liding dicho"om! diff er en"ia"ed accor ding "o progno"ic ri. ) (alue were 4aed on a

#ochr an Man"el aen7el chi9Juar e "e" wi"h adju"men" for geographic region 5'ia, Europe, Nor"h 'mer ica,

and &ou"h 'mer ica6.

T':le 3# Ade/9e Een9 -n 8e S'e *&6.l'-&n A;;&/d-ng & O/g'n Cl'99 'nd */ee//ed Te/#<

Een */&ge9e/&ne =N > $(!? *l';e:& =N > $@3?

no. of patients (% no. of e!ents no. of patients (% no. of e!ents

'n! e(en" 5>2 :<.<6 %025 5<0 :<.>6 %01>

*lood or l!mpha"ic !"em diorder 1:% 82.;6 25: 211 8;.26 2>2

#ardiac diorder 188 22.86 15: 12: 22.16 15<

Endocrine diorder %% <.%6 %5 52 >.:6 5%

/a"roin"e"inal diorder 1>% 80.:6 285 1>; 81.:6 25%

+nfec"ion or infe"a"ion 8>: ;5.86 5:: %00 ;>.;6 ;0%

)neumonia 20> 8%.:6 221 222 8>.16 28:

&epi %; <.<6 %> %0 ;.:6 %0

rinar! "rac" infec"ion 2> %.<6 80 8; ;.26 8;

Ner(ou !"em diorder 2;; %%.;6 %50 2%; %2.26 8>:

*rain edema 82 5.%6 8% 2> %.>6 80

+n"racranial preure increaed 180 21.>6 1:; 18< 28.56 1;8

3 The afe"! popula"ion included all par"icipan" who underwen" randomi7a"ion and recei(ed a" lea" one doe of "he"ud! drug. The pecific ad(ere e(en" li"ed are "hoe "ha" occurred during "rea"men" in more "han 5C of all "he "ud!

pa"ien".

n engl j med 8<1B2; nejm.org decem4er 25, 201% 2%<5




"he )-ATE#T +++ "rial,15 hould "imula"e a

r e9 "hining of procedure for drug de(elo pmen"

and "e"ing in T*+.

&uppor"ed 4! *- )harma, a di(iion of *ein eal"hcare.

Dicloure form pr o(ided 4! "he au"hor are a(aila4le wi"h

"he full "eL" of "hi ar"icle a" NEJM.or g.

e "han "he "ud! coordina"or, "he neurourgical "aff

mem9 4er, "he in"eni(e car e uni" nure and ph!ician, "he

"aff of )-' eal"h &cience and +N# -eearch, and "he

pa"ien" and familie who par"icipa"ed in "hi "rialB and Dr.

ong &un 5ni(er9 i"! opi"al 'n"werp6 for addi"ional

eL plor a"or ! anal!e.Thi ar"icle i dedica"ed "o "he memor ! of Dr . 'n"hon! Mar9

marou, who par"icipa"ed in "he deign and ini"ial conduc" of

"hi "r ial.

RE,ER ENCE S

1# Trauma"ic 4rain injur! in "he ni"ed

&"a"e emer genc! depar"men" (ii", ho9

pi"ali7a" ion and dea"h 2002200;.

'"9 lan"a #en"er for Dieae #on"rol

and )r e(en"ion, Na"ional #en"er for

+njur! )r e(en"ion and #on"rol, 2010

5h"" p\\

ww w.cdc.g o(\"rau ma"ic 4rainin jur!\p df\

4lue]4oo.pdf 6.

2# #oronado G/, Mc/uire #,

&armien9 "o , e" al. Trend in "rauma"ic

4rain in9 jur! in "he .&. and "he pu4lic

heal"h re9 pone 1::59200:. J &af e"!

- e 2012B%82::980<.

3# Maa '+, &"ocche""i N, *ulloc -.

Modera"e and e(ere "rauma"ic 4rain

in9 jur ! in adul". ance" Neur ol

200>B<<2>9

%1.4# -oo7en4ee *, Maa '+, Menon D.

#hanging pa""er n in "he e pidemiolog! of

"rauma"ic 4rain in jur !. Na" -e( Neur ol

2018B:2819;.

$# &aa"man E, Duhaime '#, *ulloc

-, Maa '+, Galada ', Manle! /T.

#laif i9 ca"ion of "rauma"ic 4rain

injur! for "ar 9 ge"ed "herapie. J

Neur o"r auma 200>B25

<1:98>.!# 'dam J, /raham D+, /ennarelli

T'. ead injur! in man and eLperimen"al

animal neur o pa"holog!. 'c"a Neur ochir

&uppl ien6 1:>8B8215980.7# Ganandingham J, #eic M, #u"ler

&, offman &, &"ein D/. Neuro"eroid

r educe inf lamma"ion af"er T*+

"hrough #D55 induc"ion. Neuroci e""

200<B%25

:%9>.

@# e J, offman &, &"ein D/.

'llo9 pregnanolone, a proge"erone

me"a 4oli"e, enhance 4eha(ior al r eco(er !

and decrea9 e neuronal lo af"er

"rauma"ic 4rain in9 jur !. -e"or Neurol

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