Cochrane Database of Systematic Reviews

Citicoline (CDP-choline) for traumatic brain injury (Protocol)

Tan HB, Wasiak J, Rosenfeld JV, O’Donohoe TJ, Gruen RL

Tan HB, Wasiak J, Rosenfeld JV, O’Donohoe TJ, Gruen RL.

Citicoline (CDP-choline) for traumatic brain injury.
Cochrane Database of Systematic Reviews 2014, Issue 8. Art. No.: CD011217.
DOI: 10.1002/14651858.CD011217.

www.cochranelibrary.com

Citicoline (CDP-choline) for traumatic brain injury (Protocol)

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Citicoline (CDP-choline) for traumatic brain injury (Protocol) i

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Protocol]

Citicoline (CDP-choline) for traumatic brain injury

Hannah Beatrix Tan1 , Jason Wasiak2 , Jeffrey V Rosenfeld3 , Tom J O’Donohoe4 , Russell L Gruen5

1 Victorian Adult Burns Service, The Alfred Hospital, Melbourne, Australia. 2 The Epworth Hospital, Richmond, Australia. 3 Professor
and Head, Department of Surgery, Central Clinical School, Monash University, Professor and Director, Department of Neurosurgery,
Alfred Hospital and Monash University, Prahran, Australia. 4 James Cook University, Townsville, Australia. 5 National Trauma Research
Institute, The Alfred Hospital, Monash University, Melbourne, Australia

Contact address: Hannah Beatrix Tan, Victorian Adult Burns Service, The Alfred Hospital, Commercial Road, Melbourne, Australia.
hbtan5@student.monash.edu.

Editorial group: Cochrane Injuries Group.

Publication status and date: New, published in Issue 8, 2014.

Citation: Tan HB, Wasiak J, Rosenfeld JV, O’Donohoe TJ, Gruen RL. Citicoline (CDP-choline) for traumatic brain injury. Cochrane
Database of Systematic Reviews 2014, Issue 8. Art. No.: CD011217. DOI: 10.1002/14651858.CD011217.

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of CDP-choline as a treatment for focal or diffuse traumatic brain injury of any severity.

BACKGROUND management of the initial pathology of TBI has proven effective

Description of the condition
Traumatic brain injury (TBI), commonly due to traffic crashes,
sports, falls and assaults, is a leading cause of death and disabil-
ity and a significant economic and social burden worldwide (Park
2008; Rosenfeld 2012). TBI is grossly classified through the Glas-
gow Coma Scale (GCS) score (out of 15) as severe TBI (GCS ≤8),
moderate (GCS 9-12) or mild (GCS 13-15) (Andriessen 2010).
The pathophysiology of TBI is due to a complex interplay be-
tween numerous cellular, inflammatory, and subcellular mecha-
nisms leading to progressive neuronal loss (Rosenfeld 2012). Pri-
mary brain injury is a result of the primary mechanical force
on brain tissues. This insult can then trigger downstream effects
(termed ’secondary brain injury’) caused by hypotension, hypoxia
and raised intracranial pressure (Andriessen 2010). Unfortunately,
despite considerable research into pre-hospital care, such as early
fluid treatment and invasive ventilatory support, no definitive
Citicoline (CDP-choline) for traumatic brain injury (Protocol)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Rosenfeld 2012).
Both primary and secondary brain injury can result in transient or
long-term dysfunction of episodic memory, attention, executive
functioning, mobility, mood and behaviour (Andriessen 2010;
Gentleman 1990; Rosenfeld 2012).
Primary prevention of trauma may limit the burden of TBI; how-
ever, treatment strategies to improve patient outcomes following
injury are still required. To date, no standard pharmacological
treatment exists to reduce the compounding effect of secondary
brain injury (Andriessen 2010; Zafonte 2009).
Description of the intervention
Cytidine 5-diphosphocholine (CDP-choline or citicoline) is a sub-
stance in the body required for synthesis of phosphatidylcholine,
a cell membrane component that is degraded during cerebral is-
chaemia, causing the release of highly toxic fatty acids and free
radicals (Fioravanti 2005).
1
CDP-choline is available in oral and enteral formulations, and has
been safely used in human trials with doses of up to 4000mg/day
with no difference in side effect profile between CDP-choline and
placebo (Zafonte 2009). In addition, pharmacokinetic data from
animals show efficient gastrointestinal absorption of the drug (
Galletti 1991). In humans, both oral and intravenous preparations
of CDP-choline are absorbed and completely converted to cytidine
and choline which circulate in plasma, crossing the blood-brain
barrier and eventually diffusing into brain tissue (Secades 2010).
A Cochrane systematic review concluded CDP-choline had a sig-
nificant effect on memory and behaviour in at least the short/
medium term in elderly people with cognitive deficits associated
with chronic cerebral disorders of the brain (Fioravanti 2005).
However, this review did not comment on the role of CDP-choline
in the treatment of TBI.
How the intervention might work
Proposed benefits of CDP-choline in patients with TBI include the
reduction of secondary injury due to cerebral oedema, reducing the
formation of harmful reactive oxygen species and lipid peroxidases,
and improving the function of cholinergic-dependent neurons.
Brain injury can result in a decrease in cell membrane phospho-
lipids leading to failure of the sodium-potassium pump, and subse-
quent intracellular accumulation of water (Calatayud Maldonado
1991). In addition, cytotoxic oedema adds to existing vaso-
genic oedema caused by breakdown of the blood brain barrier
(Calatayud Maldonado 1991). Pharmacokinetic experiments in
dogs and rats shows rapid salvage of choline into membrane phos-
pholipids in various organs (Galletti 1991). The brain demon-
strated a modest uptake of CDP-choline; however these exper-
iments were able to confirm the molecule can play a role in
restoring the structural integrity of membranes impaired by TBI
(Galletti 1991). In a human study of 78 patients (Lozano 1991),
CDP-choline was significantly associated with improved cerebral
oedema (P value < 0.005) and shorter hospital length of stay (P
value < 0.001) in patients with initial GCS of 5-7.
Exogenous administration of CDP-choline in humans has shown
an increase in glutathione, a powerful endogenous antioxidant,
while also attenuating the release of arachidonic acid, cardiolipin,
and sphingomyelin (Zafonte 2009). Animal studies have con-
firmed this improves free fatty acid concentration, decreases neu-
rological deficits, and improves behavioural performance on learn-
ing and memory tasks (Zafonte 2009).
The hippocampus and limbic system are rich in cholinergic neu-
rons and are also highly susceptible to traumatic hypoxic injury
(Poole 2008). These regions are implicated in new learning, at-
tention and retrieval. Cholinergic agents may have a role in im-
proving memory and psychosocial outcomes following traumatic
brain injury, and this is supported by findings in animal stud-
ies (Poole 2008). Large European studies have also shown CDP-
choline improves quality of survival, more frequent social and fa-
Citicoline (CDP-choline) for traumatic brain injury (Protocol)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
milial reinsertion, return to work and better response in recovery
from intellectual disorders and motor deficits (Secades 2010).
A recent systematic review concluded that administration of CDP-
choline in patients with TBI is associated with “accelerated recov-
ery from post-traumatic coma and improved gait, achieving an
improved final functional outcome and shortening hospital stays
in these patients” (Secades 2010).
Why it is important to do this review
A review evaluating CDP-choline as an intervention for TBI is
important to determine whether it does mitigate the mortality
and morbidity associated with TBI. The benefits of CDP-choline
has been addressed previously (Secades 2010); however, many in-
cluded studies had mixed patient populations and small sample
sizes. In addition, our review hopes to determine which degree
of TBI severity will receive the most benefit from CDP-choline
treatment.
OBJECTIVES
To assess the effects of CDP-choline as a treatment for focal or
diffuse traumatic brain injury of any severity.
METHODS
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs).
Types of participants
We will include studies of people of any age with focal or diffuse
TBI of any severity (mild, moderate, or severe).
Types of interventions
We will include CDP-choline administered at any dose, any fre-
quency (including continuous administration), any mode (enteral,
intravenous, etc), for any duration of time.
We will look at studies which employ a placebo or no placebo as
comparison. We will include co-interventions provided that there
is an appropriate comparison group receiving that co-intervention
alone.
2
Types of outcome measures
Primary outcomes
• Mortality
• Disability as measured by GOS/GOSE
Secondary outcomes
• Disability as measured by Functional Independence
Measure (FIM), Disability Rating Scale (DRS), or modified
Rankin Score (mRS)
• Any adverse events (e.g. restlessness or gastrointestinal side
effects)
Search methods for identification of studies
In order to reduce publication and retrieval bias we will not restrict
our search by language, date or publication status.
Electronic searches
We will seek support from the Cochrane Injuries Group Tri-
als Search Co-ordinator to design and run searches in electronic
databases. The Cochrane Injuries Group Trials Search Co-ordina-
tor will search the following:
1. the Cochrane Injuries Group specialised register (present
version);
2. the Cochrane Central Register of Controlled Trials
(CENTRAL, The Cochrane Library) (latest issue);
3. Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process &
Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and
Ovid OLDMEDLINE(R) (1946 to present);
4. EMBASE Classic + EMBASE (OvidSP) (1947 to present);
5. ISI Web of Science: Science Citation Index Expanded (SCI-
EXPANDED) (1970 to present);
6. ISI Web of Science: Conference Proceedings Citation
Index-Science (CPCI-S) (1990 to present);
7. Clinicaltrial.gov (http://www.clinicaltrials.gov/);
8. the World Health Organization (WHO) International
Clinical Trials Registry Platform (ICTRP) search portal (http://
apps.who.int/trialsearch/);
9. the European Union Clinical Trials Register (https://
www.clinicaltrialsregister.eu/).
We will adapt the MEDLINE search strategy as illustrated in
Appendix 1 as necessary for each of the other databases: the added
study filter is a modified version of the Ovid MEDLINE Cochrane
Highly Sensitive Search Strategy for identifying randomised trials
(Lefebvre 2011); for EMBASE, we will add to the search strategy
study design terms as used by the UK Cochrane Centre (Lefebvre
2011).
Citicoline (CDP-choline) for traumatic brain injury (Protocol)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Searching other resources
We will screen reference lists of relevant articles to identify any
additional potential studies for inclusion. We will also contact au-
thors of relevant trials for further information or any unpublished
data.
Data collection and analysis
Selection of studies
Two review authors (HT, TO) will independently screen the titles
and abstracts of citations from the search results to identify studies
potentially eligible for inclusion in the review. We will obtain full-
text articles for further assessment and the two review authors will
independently apply the selection criteria to determine whether
a study is eligible for inclusion. We will resolve disagreements
regarding study eligibility through discussion and if necessary by
consulting a third author (JW) for a final decision.
We will include a flow diagram outlining the study selection pro-
cess in the final review as recommended in the Preferred Report-
ing Items for Systematic Reviews and Meta-Analyses (PRISMA)
statement (Moher 2009).
Data extraction and management
Two independent review authors (HT, TO) will assess each in-
cluded study using a standardised data extraction form specifically
designed and piloted for this review. We will resolve discrepancies
in data extraction through discussion or by consulting a third au-
thor (JW) for a final decision. When a study is reported in more
than one paper, we will extract data from the most relevant pa-
per that has been published. One review author (TO) will enter
data from the included studies into the Cochrane Collaboration’s
statistical software, Review Manager 2014, and a second review
author (HT) will independently check all data entries.
We will collect the following general information from the in-
cluded studies.
• General information regarding publication: author, title,
date of publication, language, country of origin, funding source,
and citation.
• Study characteristics: study design, method of
randomisation (sequence generation, concealment of allocation),
blinding of outcomes, setting.
• Participants: sample size, sample size power calculation (if
performed), number of participants randomised to each group,
inclusion criteria, exclusion criteria, severity of TBI, presence of
additional injuries, demographic data, any baseline difference
between treatment groups, dropouts, losses to follow up.
• Intervention: dose of CDP-choline used, route of
administration, timing and duration of treatment.
3
 • Comparison: description of placebo or non-placebo control
group
• Outcomes: incidence of mortality and any adverse events,
assessment of disability, secondary outcomes, and timing of
outcome assessment
We will record the number of participants assessed for each out-
come. For continuous data, we will collect mean values and stan-
dard deviations (SDs) where available. For dichotomous data, we
will collect the number of events in each group. In addition, we
will collect any summary statistics provided by trialists for primary
or secondary outcomes (e.g. effect estimates, confidence intervals
(CIs), standard errors (SEs), P values, ranges).
Assessment of risk of bias in included studies
Two review authors (HT, TO), will independently assess the risk
of bias of the eligible trials. We will base our assessment on the
guidance in the Cochrane Handbook for Systematic Reviews of Inter-
ventions (Higgins 2011). We will resolve disagreements by a con-
sensus meeting with a third review author (JW). In the case of
discrepancies, we will contact the authors of the paper for clarifi-
cation or missing information. We will assess and summarise the
potential risk of bias for each trial by using the Cochrane Collab-
oration’s tool for assessing risk of bias (Higgins 2011).
Measures of treatment effect
If possible, we will calculate the risk ratios (RRs) and 95% CIs
for every categorical outcome measured in two or more studies
evaluating the same treatment. For continuous outcomes, we will
present data as point estimates with 95% CIs. We will present re-
sults for continuous outcomes as mean differences (MDs) if out-
comes included in a meta-analysis are measured using the same
scale; if outcomes are measured using different scales, we will pool
the data using standardised mean differences (SMDs). We will re-
port the 95% CIs for each measure of effect. There is a possibility
that all the identified studies will not be comparable. If this is the
case, we will report a qualitative description of all identified stud-
ies.
Unit of analysis issues
We will consider the participant as the unit of analysis.
Dealing with missing data
We will attempt to contact study authors to obtain any missing in-
formation. Where appropriate, we will impute missing data based
on the information available. For continuous measures, missing
SD values will be imputed from other measures such as SEs, CIs
or P values or we will use SDs based on similar trials. For dichoto-
mous outcomes, proportions or percentages will be used to esti-
mate the number of events or the number of people assessed for
Citicoline (CDP-choline) for traumatic brain injury (Protocol)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
an outcome. We will record all data imputations in the ’Charac-
teristics of Included Studies’ tables.
We will consider the potential impact of missing data when we
interpret results for the review.
Assessment of heterogeneity
We will assess statistical heterogeneity using the Chi2 test (we will
consider a P value significance level of less than 0.1 to indicate
heterogeneity). We will consider the I2 statistic which examines
the percentage of total variation across studies due to heterogene-
ity rather than to chance. We intend to use a fixed-effect model
of analysis (Greenland 1985). Values of I2 over 50% may rep-
resent substantial heterogeneity (Deeks 2011), and if substantial
heterogeneity is identified, we may use a random-effects model
(DerSimonian 1986).
Assessment of reporting biases
If more than 10 studies are identified, we will perform funnel
plots and a linear regression test to examine the likely presence
of reporting bias in meta-analysis (Egger 1997). We will consider
a P value of less than 0.1 as statistically significant for the linear
regression test.
Data synthesis
If the included trials are both clinically and statistically homoge-
neous, a meta-analysis can be conducted to obtain an overall effect.
We plan to pool the data for both dichotomous and continuous
outcomes using a fixed-effect model in the first instance. In the
presence of substantial heterogeneity we may use a random-effects
model. We will perform all analyses using Review Manager 2014.
Subgroup analysis and investigation of heterogeneity
We will perform subgroup analysis subject to data availability.
As this review aims to identify which degree of TBI severity will
receive the most benefit from CDP-choline treatment, we will
conduct subgroup analyses according to:
• severity of traumatic brain injury (mild, moderate or
severe),
• route of administration (oral or parenteral),
• dosage (higher or lower), and
• duration of treatment (short treatment ≤ 30 days or long
treatment >30 days).
Sensitivity analysis
We will perform sensitivity analyses in order to explore the quality
of allocation concealment (low risk of bias versus unclear or high
risk of bias).
4
ACKNOWLEDGEMENTS
Ornella Clavisi, for reviewing the protocol and general support.
REFERENCES
Additional references
Andriessen 2010
Andriessen TM, Jacobs B, Vos PE. Clinical characteristics
and pathophysiological mechanisms of focal and diffuse
traumatic brain injury. Journal of Cellular and Molecular
Medicine 2010;14(10):2381–92.
Calatayud Maldonado 1991
Calatayud Maldonado V, Calatayud Pérez JB, Aso Escario
J. Effects of CDP-choline on the recovery of patients with
head injury. Journal of the Neurological Sciences 1991;103
Suppl:S15–8.
Deeks 2011
Deeks J, Higgins JPT, Altman DG (editors). Chapter 9:
Analysing data and undertaking meta-analysis. In: Higgins
JPT, Green S (editors). Cochrane Handbook for Systematic
Reviews of Interventions Version 5.1.0 (updated March
2011). The Cochrane Collaboration, 2011. Available from
www.cochrane-handbook.org.
DerSimonian 1986
DerSimonian R, Laird N. Meta-analysis in clinical trials.
Controlled Clinical Trials 1986;7(3):177–88.
Egger 1997
Egger M, Davey Smith G, Schneider M, Minder C. Bias
in meta-analysis detected by a simple graphical test. BMJ
1997;315(7109):629–34.
Fioravanti 2005
Fioravanti M, Yanagi M. Cytidinediphosphocholine
(CDP-choline) for cognitive and behavioural disturbances
associated with chronic cerebral disorders in the elderly.
Cochrane Database of Systematic Reviews 2005, Issue 2.
[DOI: 10.1002/14651858.CD000269.pub3]
Galletti 1991
Galletti P, De Rosa M, Cotticelli MG, Morana A, Vaccaro R,
Zappia V. Biochemical rationale for the use of CDPcholine
in traumatic brain injury: pharmacokinetics of the orally
administered drug. Journal of the Neurological Sciences 1991;
103 Suppl:S19–25.
Gentleman 1990
Gentleman D. Preventing secondary brain damage after
head injury: a multidisciplinary challenge. Injury 1990;21:
305–8.
Greenland 1985
Greenland S, Robins JM. Estimation of a common effect
parameter from sparse follow-up data. Biometrics 1985;41
(1):55–68.
Higgins 2011
Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8:
Assessing risk of bias. In: Higgins JPT, Green S (editors).
Citicoline (CDP-choline) for traumatic brain injury (Protocol)
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Cochrane Handbook for Systematic Reviews of Interventions
Version 5.1.0 (updated March 2011). The Cochrane
Collaboration, 2011. Available from www.cochrane-
handbook.org.
Lefebvre 2011
Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching
for studies. In: Higgins JPT, Green S (editors). Cochrane
Handbook for Systematic Reviews of Interventions. Version
5.1.0 (updated March 2011). The Cochrane Collaboration,
2011. Available from www.cochrane-handbook.org.
Lozano 1991
Lozano R. CDP-choline in the treatment of cranio-
encephalic traumata. Journal of the Neurological Sciences
1991;103 Suppl:S43–7.
Moher 2009
Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA
Group. Preferred reporting items for systematic reviews
and meta-analyses: the PRISMA statement. PLoS Medicine
2009;6(7):e1000097.
Park 2008
Park E, Bell JD, Baker AJ. Traumatic brain injury: Can the
consequences be stopped?. Canadian Medical Association
Journal 2008;178(9):1163–70.
Poole 2008
Poole NA, Agrawal N. Cholinomimetic agents and
neurocognitive impairment following head injury: a
systematic review. Brain Injury 2008;22(7-8):519–34.
Review Manager 2014 [Computer program]
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Rosenfeld 2012
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MC, Manley GT, Gruen RL. Early management of severe
traumatic brain injury. Lancet 2012;380(9847):1088–98.
Secades 2010
Secades JJ. Citicoline: pharmacological and clinical review,
2010 update. Revista de Neurología 2011;52 Suppl 2:
S1–S62.
Zafonte 2009
Zafonte R, Friedewald WT, Lee SM, Levin B, Diaz-
Arrastia R, Ansel B, et al. The citicoline brain injury
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∗
Indicates the major publication for the study
5
APPENDICES

Appendix 1. MEDLINE search strategy

1. exp CRANIOCEREBRAL TRAUMA/
2. exp Cerebrovascular Trauma/
3. exp BRAIN EDEMA/
4. ((brain or cerebral or intracranial) adj3 (oedema or edema or swell$)).ab,ti.
5. exp GLASGOW COMA SCALE/
6. exp GLASGOW OUTCOME SCALE/
7. exp UNCONSCIOUSNESS/
8. (Glasgow adj3 (coma or outcome) adj3 (scale$ or score$)).ab,ti.
9. (Unconscious$ or coma$ or concuss$ or ’persistent vegetative state’).ab,ti.
10. “Rancho Los Amigos Scale”.ab,ti.
11. ((head or crani$ or cerebr$ or capitis or brain$ or forebrain$ or skull$ or hemispher$ or intra-cran$ or inter-cran$) adj3 (injur$ or
trauma$ or damag$ or wound$ or fracture$ or contusion$)).ab,ti.
12. “Diffuse axonal injur$”.ab,ti.
13. ((head or crani$ or cerebr$ or brain$ or intra-cran$ or inter-cran$) adj3 (haematoma$ or hematoma$ or haemorrhag$ or hemorrhag$
or bleed$ or pressure)).ab,ti.
14. or/1-13
15. randomi?ed.ab,ti.
16. randomized controlled trial.pt.
17. controlled clinical trial.pt.
18. placebo.ab.
19. clinical trials as topic.sh.
20. randomly.ab.
21. trial.ti.
22. Comparative Study/
23. 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22
24. (animals not (humans and animals)).sh.
25. 23 not 24
26. 14 and 25
27. Cytidine Diphosphate Choline/
28. citicoline.ab,ti.
29. cdp-choline.ab,ti.
30. cytidine-5-diphosphocholine.ab,ti.
31. (“cdp choline” or cdpcholine).ab,ti.
32. 27 or 28 or 29 or 30 or 31
33. 26 and 32

CONTRIBUTIONS OF AUTHORS
Russell Gruen: Protocol development.
Tom O’Donohoe: Protocol development.
Jeffrey Rosenfeld: Protocol development.
Hannah Beatrix Tan: Protocol development.
Jason Wasiak: Protocol development.

Citicoline (CDP-choline) for traumatic brain injury (Protocol) 6

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DECLARATIONS OF INTEREST
Russell Gruen: None known.
Tom O’Donohoe: None known.
Jeffrey Rosenfeld: None known.
Hannah Beatrix Tan: None known.
Jason Wasiak: None known.

Citicoline (CDP-choline) for traumatic brain injury (Protocol) 7

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.