Citi func

8/18/2019 Citi func

1/9

ORIGINAL CONTRIBUTION

of

C iticoline on Functiona l

d C ogn it ive Status Am on g Pat ients

i t h Traum atic Brain Injury

s D. Zafonte, DO

vack, PhD

Hesdorffer, PhD

R. Temkin, PhD

ESPITE CONSID ERABLE AD-

vances in emergency and

critical care management of

traumatic brain injury (TBI)'

ts for neuroprotection or en-

ed recovery, ̂no effective pharma-

been identified.

p 2 0 3 2 .

C o n t e x t Traumatic brain injury (TBI) is a serious public health problem In the United

States, yet no treatment is currently available to improve outcome after TBI. Ap-

proved

for

use

in

TBI

in 59

countries, citicoline

is

an endogenous substance offering

potential neuroprotective properties as well as facilitated neurorepair post injury.

O b jec t i v e To determine the ability of citicoline to positively affect functional and

cognitive status in persons with complicated mild, m oderate, and severe TBI.

D es i gn S e t t i ng an d P a t i en t s The Citicoline Brain Injury Treatment

Trial

(COBRIT),

a phase

3,

double-blind randomized clinical trial conducted between July 20, 2007,

and February 4, 2011 , among 1213 patients at 8 US level 1 trauma centers to inves-

tigate effects of citicoline vs placebo in patients wit h TBI classified as com plicated mild,

moderate, or severe.

i n t e r v e n t i o n Ninety-day regimen of daily enterai or oral citicoline (2000 mg) or pla-

cebo.

M a i n O u t c o m e M e a s u r e s Functional and cognitive status, assessed at 90 days

using the TBI-Clinical Trials Network Core Battery.

A

global statistical test was used

to

analyze the 9 scales of the core battery. Secondary outcomes were func tional and cog -

nitive imp roveme nt, assessed

at

30, 90 , and 1 80 days, and examination

of

the

long-

term maintenance of treatment effects.

Resul ts Rates

of

favorable improvem ent for the G lasgow Outcom e Scale-Extended

were 35.4 in the citicoline group and 35.6 in the placebo group. For all other scales

the rate of improvement ranged from 37.3 to 86.5 in the citicoline group and

from 42.7 to 84.0 in the placebo group. The citicoline and placebo groups did

not differ significantly at the 90-day evaluation (global odds ratio [OR], 0.98 [95

CI,

0.83-1.15]);

in

addition, there was no s ignificant treatm ent e ffect in the 2 severity

subgroups (global OR, 1.14 [95 CI, 0.88-1.49] and 0.89 [95 CI, 0.72-1.49] for

moderate/severe and complicated m ild TBI, respectively). At the 1 80-day evaluation,

the citicoline and placebo groups did not differ significantly with respect to the pri-

mary outcome (global OR,

0.87

[95 CI, 0.72-1 .04]).

Conc lus ion Am ong patients with traumatic brain injury, the use of citicoline com -

pared w ith placebo for 90 days did not result in improvement in functional and cog-

nitive status.

Tr i a l Reg is t ra t ion clinicaltrials.gov Identifier: NCT00545662

JAMA. 2012;308 19):1993-2000

www.jama.com

pleiotropic range of neuroprotective

properties' '^ and is an approved

therapy for TBI in 59 countries.'̂ Citi-

coline is also widely available in tbe

United States as a nutraceutical and is

Author Affi l iations

are

listed

at the end of

this

ar-

ticie.

Corresponding

Author oss

D. Zafonte, DO, Spauld-

ing Rehabilitation Hospital Networi

8/18/2019 Citi func

2/9

USE OF CITICOLINE IN TRAUMATIC BRAIN INJURY

used by patients with a range of neu-

rologic disorders, yet it has not been

evaluated in a large randomized clini-

cal trial for TBI. Therefore, we evalu-

ated the efficacy of citicoline for im-

proving cognitive and functional status

amon g patients vnth TBI.

Animal and human studies suggest

a wide window of opportunity for neu-

roprotection and neurologic recovery

with citicoline, ranging from 6 hours

to mo re than 4 8 hours'** post TBI. We

examined the effects of 90 days of oral

citicoline vs placebo initiated within 24

hours of injury in patients with com-

plicated

mild

mod erate, and severe TBI.

This

is,

to our knowledge, the first ne u-

roprotection study to include compli-

cated mild

TBI,

an important group be-

cause such patients have evidence of

cognitive dysfunction and are more

similar to those with moderate TBI than

to those with mild

METHODS

Patients and Sites

The Citicoline Brain Injury Treatment

Trial (COBRIT) is a multicenter, pla-

cebo-control led, 2-group, phase 3,

double-blind randomized clinical trial

conducted at 8 US level 1 trauma cen-

ters.

These centers follow

a

large num -

ber of patients with TBI through acute,

intermediate, and rehabilitation care

and provided an ethnically and dem o-

graphically diverse patient population

(TABLE 1).

All participants required inpatient

acute hospi ta l izat ion. The inst i tu-

tional review boards of all participat-

ing sites approved the protocol and

either the patients or their legally au-

thorized representatives provided writ-

ten informed consent according to the

local institutional review board rules for

proxy consent. If an authorized repre-

sentative provided consent originally,

the participant directly provided con-

sent for continued involvement on re-

covery of decision-making capacity.

Neuroimaging entry criteria were

verified by the neurosurgical team at

each participating

site.

Clinical ca re fol-

lowed set protocols established by the

study network for acute and postacute

interventions, based on the American

Academy of Neurological Surgeons

acute care guidelines and a co nsensus

of rehabilitation experts for postacute

protocols.'

inclusion and Exclusion riteria

Patients were aged 18 (19 in Ala-

bama) to 70 years and had a nonpen-

etrating TBI. Glasgow Coma Scale

(GCS) scores obtained without para-

lytic treatment were 3 to 12 with mo-

tor score of

5

or less, 3 to 12 with mo -

tor score of 6 and meeting any of the

compu ted tomography (CT) criteria, or

13 to 15 and m eeting any of the CT cri-

teria. GCS scores obtained with para-

lytic treatment were GCS 3TP (intu-

bated and paralyzed) m eeting any of the

CT scan criteria. Neuroimaging crite-

ria were 10 mm or greater total diam-

eter of all intraparenchymal hemor-

rhages, acute extra-axial hematoma

thickness of 5 mm or greater, subarach-

noid hemorrhage visible on at least 2

contiguous 5-mm slices or at least 3

contiguous 3-mm slices, intraventricu-

lar hemorrhage present on 2 slices, or

midline shift of 5 mm or greater.

Eligibility exclusion s were any of the

following: bilaterally fixed and dilated

pupils, positive pregnancy test result or

known pregnancy, imminent death or

current life-threatening disease, pris-

oner, currently enrolled in another

study, acetylcholinesterase inhibito r use

within th 2 weeks prior to injury, or

evidence of serious psychiatric and n eu-

rologic disorders tha t interfere with o ut-

come assessment.

An external data and safety moni-

toring committee provided indepen-

dent oversight.

A

data coordinating cen-

ter at Columbia University stored and

analyzed all data.

Study Procedures

Patients were randomly assigned in a

1:1 ratio to receive a 90-day regim en of

either citicoline (2000 mg/d) or pla-

cebo via enterai route, initiated within

24 hours of injury. Pat ients were

screened for medical history by the

study coordinator as well as the neu-

rosurgery or trauma team, according to

the inclusion and exclusion criter

Part ic ipants unable to swallow r

ceived medicat ion in the form

crushed tablets and either water

25-mL saline flush via a nasoga stric

percu taneous endoscopie gas t ro

tomy tube. Treatment was given on

if patients were able to receive me

cation by either method . Ferrer Gru

provided citicoline and identical p

cebo,

distributed to the clinical sites

a cen t ra l d rug d i s t r ibu t ion cen t

(ALMAC). Patients, coordinators, ph

sicians, and outcome evaluators we

blinded to the treatment assignme

Randomization was stratified by site a

severity of injury, measu red by pre ra

domizat ion GCS, and implemen t

through WebFZ, the randomizati

system provided by ALMAC.

Baseline CT scans, vital signs, p

ticipant medical history, demograp

ics,

and in ju ry in format ion we

obtained and reviewed prior to ra

domization. Race and ethnicity we

self-reported and recorded according

the National Institutes of Health cla

sification. Information con cerning oth

medical treatments, including surg

cal interventions, in-dep th injury inf

mation, changes in clinical status, a

vital signs, were collected within

hours after randomization. Surgic

interventions, concomitant medic

tions, GCS scores, CT scan

results,

a

neurologic worsening were collected

days 2 through 7 of hospitalization

well.

Vital signs were recorded every

hours during the first 7 days of hosp

talization and then at the 30- and 9

day outcome

visits.

M etabolic, liver, a

hématologie functions were m easur

at baseline and day 3, and at 30- a

90-day visits via blood samples. A

verse symptoms and events were r

corded at regularly scheduled pe

sona l and te lephone con tac t s a

during outcome visits at days 14, 3

58 ,

90, 135, and 180.

The primary outcome of this stu

was functional status and cogn itive p

formance at 90 days, measured by t

9 comp onents of the TBI Clinical Tri

Netw ork Core Battery.'® T he batte ry i

19 94 JAMA, November 21, 2012—Vol 308, No. 19

8/18/2019 Citi func

3/9

USE OE CITICOLINE IN TRAUMATIC BRAIN INJURY

d B '̂-^ ; the Glasgow Outcome Scale-

Association Test̂ ^ the Cali-

ia Verbal Learning Test I P ; the Pro-

IIP'*;

and S troop Test Parts

an d

The GOS-E was dichotomized as 1

8 for good outcome. T his cut-

f was set because of the high prop or-

easures in the battery are con-

standard deviation less than the

ere neurologically impaired at

e assess-

e category. Normative data were

Secondary outcomes w ere the recov-

f cognitive and functional abilities

a battery of tests administered at

, 90, and 180 days postrandomiza-

of disability, life satisfaction, and

l well-being at 30, 90 , and

that the treat-

nt effect is constant across all mea-

fect size is establishe d, the global test

tests the null hypothesis that

mo n effect size is zero against

an alternative hypothesis that the com-

mon effect size is different from zero.

The use of a global test proced ure to si-

multaneously test several outcomes is

not

new ̂ '̂ *

and has been used, for ex-

ample, in trials of stroke.^'

In COBRIT, the global statistic esti-

mates the odds ratio (OR) for a good

Table 1 . Baseline Characteristics, Interventions (N = 1213)

No. (%)

Characterist ic

Citicoline

(n = 607

Age,

y

18-30 235 (38.7)

>30-45

122(20.1)

>45-60

160(26.4)

> 6 0 90(14.8)

Sex

Women

151 (24.9)

Me n

456 (75.1)

Education

High school 290 (47.8)

College or trade school 284 (46.8)

Graduate school 24 (4.0)

Missing

9(1.5)

Moderate/severe 204 (33.6)

Head AIS

168(27.9)

Placebo

= 606

199(32.8) '

142(23.4)

184(30.4)

81 (13.4) J

159(26.2)-]

447 (73.8) J

290 (47.8)

275 (45.4)

31 (5.1)

10(1.6) J

Traumatic brain injury severity by GCS Sc ore ''

Comp licated mild 403 (66.4) 404 (66.7) ~|

202 (33.3) J

171 (28.5)

P

Value^

.08

.60

Race/ethnicity

White

Black or African American

Hispanic

Other

Missing

480(79.1)

84(13.8)

21 (3.5)

21 (3.5)

1 (0.2)

477 (78.7) ~

90(14.8)

28 (4.6)

11(1.8)

0 J

.23

.78

.95

Mechanism of injury

Motor vehicle (driver/passenger)

Struck by vehicle

Fall

Sports

Assault

ether mechanism

304 (50.1)

34 (5.6)

179(29.5)

3 (0.5)

58 (9.6)

29 (4.8)

290 (47.8) -|

38 (6.3)

199(32.8)

4 (0.7)

55 (9.1)

20(3.3) _

63

81

> 4

Posttraumatic amnesia duration, h

s 2 4

> 2 4

Neurosurgery

No

Yes

Intracranial pressure monitoring

No

Yes

Brain tissue oxygen monitoring

No

Yes

Ventriculostomy

No

Yes

435(72.1)

126(26.6)

348 (73.4)

492(81.0)

115(19.0)

516(85.0)

91 (15.0)

560 (92.3)

47 (7.7)

503 (82.9)

104(17.1)

429(71.5) J

121 (25.8) -]

347 (74.2) J

491 (81 .0) - |

115(19.0) J

517(85.3) ]

89(14.7) J

560 (92.4) ~|

46(7.6) J

501 (82.7) -1

105(17.3) J

/Abbreviations:

AIS,

Abbreviated Injury

Score; GCS,

Glasgow Coma

Scale;

OR, odds ratio,

^By Fisher exact test.

''Score ranges rom

3

through

5

for complicated mild and rom 3 through

2

for moderate/severe.

> QQ

94

^ QQ

94

JAMA, November 21 , 2012—V ol 308, No. 19 1 9 9 5

8/18/2019 Citi func

4/9


Fig ure 1 . COBRIT Study Flow

1181 2 Patients screened for eligibility

10599 Excluded

2003

803

683

671

539

388

5341

Age >70 y

Out of study time window

Refused consent

Unabie to provide consent

GCS improved

Non-English speaking

Other

607 Randomized to receive citicoline

267 Took ä75 of doses

249 Took

8/18/2019 Citi func

5/9

USE OE CITICOLINE IN TRAUMATIC BRAIN INJURY

al was stopped on February 7,2 01 1.

s underw ent follow-up u nul M ay

the date at which the last ran-

e assessment. The primary 90-

me was available for 996 pa-

and the 180-day outcome was

between July

,

2007, and February

4, 2011.

Of the

12 pa tients consecutively screened,

ts enrolled, 606 (50 ) were ran-

to the placebo group and 607

) to the citicoline

group.

As is typi-

TBI studies, more than half of par-

were men (Table 1 ). Ap-

es, and approxi-

26 had a posttraum atic am-

a duration of 24 hours or

less.

The

ine and placebo gro ups were simi-

cs (Table 1). Groups we re also simi-

ng surgical interventions an d

l bu t 6 patients received at least dose

om random ization to adm inistration

rst dose was 1.6 a nd 1.8 ho urs

first dose within

hours of injury. Five hund red thirty-

patients (44 ) were adhere nt and

40.7 ) were nonadherent; adher-

was unk now n for 181 (14.9 ).

ith respect to the TBI

l OR, 0 .98 [95 CI, 0 .8 3-

Because the global null h ypoth-

Table 2. Results for the Primary Analysis: 90-Day Evaluation^

Measure

Global Test

Glasgow Outcome

Scale-Extended

California Verbal Learning Test

Processing Speed Index

Trail Making A

Trail Making B

Digit Span

Stroop Part 1

Stroop Part 2

Controlled Cral Word

Association Test

Model stratified by GCS score*^

Moderate/severe

Complicated mild

Model stratified by GC S score

adjusted for tiead AIS

Moderate/severe

Complicated mild

Favorable Outcome,

No. ( )

1

Citicoline

(n = 508)''

180(35.4)

262 (57.7)

236 (52.7)

291 (65.0)

332 (74.4)

391 (86.5)

288 (65.3)

295 (68.3)

178(37.3)

1

Placebo

= 509)

181 (35.6)

280 (60.5)

244 (53.3)

285 (62.0)

324(71.1)

389 (84.0)

299 (68.0)

289 (66.6)

207 (42.7)

OR (95 Cl)

0.98 0.83-1.15

0.99

0.89

0.98

1.14

1.19

1.22

0.89

1.08

0.80

1.14 0.88-1.49

0.89 (0.72-1.08)

1.14 0.88-1.48

0.92 0.75-1.12

P

Value

.76

.31

.12

.32

.18

Abbreviations: AIS, Abbreviated Injury Score; GCS , Glasgow Com a Scaie; OR, odds ratio.

^All models are adjusted tor clinical site.

Cutpoints tor definition ot good outcom e: greater than 6 tor Glasgow Outcom e Scale-Extended: greater than 36 tor Cali-

tomia Verbal Leaming Test; greater than 85 for P rocessing Speed index; less than 42.33 tor Trail Mai

8/18/2019 Citi func

6/9

U OF CITICOLINE IN TRAUMATIC BRAIN INJURY

(P=.17) (FIGURE 2). Among patients

with moderate/severe TBI, 34 of 202

(16.8 ) in the placebo g roup and 25

of

204

(12.2 )

in the

c i t i c o l i n e

group died, with 31 (91.2 ) in the

placebo group

and 24

(96.0 )

in the

citicoline group dying within

the

first

30 days. Among patients with

com-

plicated mild TBI,

8 of

404 (2.0 )

in

t h e p l a c e b o g r o u p

and 6 of 403

(1.5 ) in the citicoline group died,

with

5

(62.5 )

in the

placebo group

an d

2

(33.3 )

in the

citicoline group

dying within tbe first 30 days. Sur-

vival curves were similar between

the

2 groups, even after stratification by

G C S s e v e r i t y

at

r a n d o m i z a t i o n

(Figure

2).

Table 3 Results

for

the Secondary

Measure

Global Test

Glasgow Outcome

Scale-extended

California Verbal Learning Test

Processing Speed Index

Trail Making A

Trail Making B

Digit Span

Stroop Part 1

Stroop Part 2

Controlled Oral Word Association

Test

Model stratitied by Glasgow Com a

Scale Score'^

Moderate/severe

Complicated miid

Model stratified

by

Glasgow Com a

Scale Score adjusted by head AIS

Moderate/severe

Complicated mild

Analysis: 180-Day Evaluat ion

Favorable Outcome,

N o.

( )

I

Cit icol ine

(n = 448) ' '

194(43.3)

240 (63.7)

223 (60.0)

257 (68.5)

276 (74.2)

325 (86.2)

232 (62.4)

253 (68.8)

180(42.4)

1

Placebo

(n = 455)

209 (45.9)

272 (69.4)

236 (60.7)

268 (68.7)

292(75.1)

334 (85.4)

258 (68.0)

281 (74.7)

219(50.0)

OR (95% CI)

0.87(0.72-1.04)

0.90

0.77

0.97

0.99

0.96

1.07

0.78

0.74

0.73

1.26(0.92-1.70)

0.72 (0.56-0.91)

1.23(0.91-1.66)

0.74 (0.58-0.94)

P

Value

.13

.14

.004

.18

.008

Abbreviations: AIS, Abbreviated Injury Score; OR, o dds ratio.

^ All models are adjusted

for

clinical site.

° Cutpoints for definition

of

good outcom e: greater than

6

for Glasgovi/ Outcom e Scale E xtended; greater th n 36 for

Cali-

fornia Verbal Learning Test; greater than

85 for

Processing S peed index; less than 42.33

for

Trail Mai

8/18/2019 Citi func

7/9


Prior studies noted difficulty with

COBRIT is among the largest

ou p as we ll as the difficulty in

The post hoc findings observed at 180

in the group with com plicated m ild

explanation is a negative ef-

less severe injury. Molecular

patients may be deleterious in the

therap y tha t affects in-

atory, lipid peroxidative, and cho-

rgic mechanisms may have less ben-

less severe injury. This stud y

ot address the effects of citicoline if

inistered earher in recovery or in ti-

does reflect present

clini-

Among 18 randomized controlled

have been negative.''*' The ab-

y simply being ineffective or

pathophysiologi-

TBI.

This would suggest

hanism s of action of drugs

TBI trials would ne ed to

ffect. F utur e studies may benefit

In conclusion, this large, random-

ized, blinded study showed that acute

and subacute treatment with citico-

line did not result in improvement in

functional and cognitive status. These

findings call into question the use of

citicoline for patients w ith TBI.

Author Affiliations:

Department of Physicai Medi-

cine and Rehabiiitation, Harvard Medical

Schooi,

and

Massachusetts Gênerai Hospitai, Boston, Massachu-

setts (Dr Zafonte ); Departm ent of Heaith Evidence and

Poiicy, Mount Sinai Schooi of Medicine, New Yori

8/18/2019 Citi func

8/9


and blood-brain barrier breakdown after traumatic

brain injury. J Neurosurg. 2000;92 3):448-452.

5. Dempsey RJ, Raghavendra Rao VL. Cytidinedi-

phosphocholine treatment to decrease traumatic brain

injury-Induced hippocampal neuronal death, cortical

contusion

volume,

and neurological dysfunction n

rats

; Neurosurg. 2003;98 4):867-873.

6. Cohadon F, Richer E, Poletto B. A precursor of phos-

pholipids in the treatme nt of severe traumatic comas.

Neurochirurgie. 1982;28 4):287-290.

7. Calatayud Maldonado V, Calatayud Pérez

JB,

Aso

Escario J. Effects of CDP-choline on the recovery of

patients with head injury. J Neuroi

Sei.

1991;103

suppl):S15-S18.

8. Levin HS. Treatment of postconcussional symp-

toms with CDP-choline. J Neuroi Sei.

1991

;103

suppl):S39-S42.

9. Kennedy EP. The synthesis of cytidln e diphos -

phate

choline,

cytidine diphosphate ethanolamine, and

related compounds. J Bioi Chem. 1956;222 1) :

185-191.

10 . Adibhatia RM, Hatcher JF. Citicoline mecha-

nisms and clinical efficacy in cerebral Ischemia. J Neu-

rosei Res. 2002;70 2):133-139.

11 .

Secades JJ. Citicoline: pharmacological and clini-

cal review, 2010 update. Re v Neuroi. 2011;52

suppl2):S1-S62.

12 .

Lozano

R.

CDP-choline in the treatment of cranio-

encephalic traumata. J Neuroi

Sei.

1991 ;103 suppl):

S43-S47.

13 . Arenth PM, Russell KC, RickerJH, Zafonte RD.

CDP-choline as a biological supplement during neu-

rorecovery: a focused review. PM R. 2011;3{6)

suppi 1):S123-S131.

14 . Alexandrov AV. Citicoline: Ferrer Internacional.

CurrOpin investig Drugs. 2001;2 12):1757-1762.

15 .

Williams DH , Levin

HS,

Eisenberg

HM .

Mild head

injury classification. Neurosurgery. 1990;27 3) :

422-428.

16.

Zafonte R, Friedewald WT , Lee SM , et

al.

The Citi-

coline Brain Injury Treatment COBRIT)

thai:

design

and methods. J Neurotrauma. 2009;26 12):2207-

2216.

17 . Brain Trauma Foundation, American Association

of Neurological Surgeons, Joint Section on Neu-

rotrauma and Cr i t ical Care. Trauma systems.

J Neurotrauma. 2000;17 6-7):457-462.

18 .

Bagiella

E,

Novack TA, Ansel B, et a l. Measuring

outcome in traumatic brain injury treatment

trials:

rec-

ommendations from the Traumatic Brain Injury Clini-

cal Trials Network. J Head Trauma Rehabii. 2010;

25 5):375-382,

19 . Reitan R. Traii Mai

Citi func

Documents

Transcript of Citi func