TXA Study Protocol 2019-518-EX PDF

Tranexamic Acid in Traumatic Brain Injury: A Systematic Review
and Metanalysis of Randomized Controlled Trials

Dr. Christopher G. Manalo, Dr. Faith Joan C. Mesa-Gaerlan, and Dr. Jorge M. Concepcion
Department of Emergency Medicine, Philippine General Hospital, University of the Philippines Manila
Corresponding investigator:
Dr. Christopher G. Manalo (cgmanalo@up.edu.ph)
ABSTRACT
This systematic review and meta-analysis protocol aims to assess the effects of tranexamic acid versus
placebo in traumatic brain injury.
BACKGROUND
Description of the condition
Traumatic brain injury is a major cause of death and disability. According to the Center for Disease Control
(CDC), an estimated 2.87 million traumatic brain injury-related emergency visits, hospitalizations, and deaths
occurred in the United States in 2014. In terms of emergency department visits, approximately 2.5 million traumatic
brain injury-related consults was recorded in the same year. This resulted to approximately 56,800 deaths from
traumatic brain injury (CDC 2019).
In the Philippines, approximately 285,035 cases or an incidence of 275 per 100,000 population of traumatic
brain injury was recorded in 2016. These numbers constitute a considerable portion of injury burden and deaths in
the country and are caused primarily by road injuries and falls (GBD 2016). Data from the Philippine General
Hospital in 2011 cited that a central nervous system (CNS) cause of death was the third most common antecedent
Tranexamic acid in traumatic brain injury: A systematic review and metanalysis of randomized controlled trials (Protocol)
Manalo CG, Mesa-Gaerlan FJC, & Concepcion JM
13 December 2019 Version 1
Protocol template from Cochrane Database of Systematic Reviews ©2013
Page 1 of 33
cause of overall traumatic death at 19% with traumatic brain injury as direct sequelae at 63% of all CNS failure
(Consunji 2011).
The disease burden of traumatic brain injury is not only brought about by mortality but also by the
debilitating after-effects of the injury. Secondary brain injury from progressive intracranial bleeding, cerebral edema,
increased intracranial pressure and subsequent cerebral ischemia is the primary cause of morbidity following a
traumatic brain injury (Zehtabchi 2013).
Description of the intervention
The hemostatic drug tranexamic acid with antifibrinolytic activity is commonly used in trauma patients.
Because of its potential role in reducing size of hematoma that prevents secondary brain injury, tranexamic acid has
been considered a possible therapeutic option to improve clinical outcomes in patients with traumatic brain injuries
(Weng 2019). However, the effect of tranexamic acid on patients with traumatic brain injury remains unclear.
How the intervention might work
Why it is important to do this review
In the past 10 years, many observational cohorts and randomized controlled trials have attempted to clarify
the beneficial effects of tranexamic acid on patient outcomes int traumatic brain injuries. By far, clinical trials have
been limited to small-sized populations. Results of systematic reviews and meta-analyses (Ayman 2018; Weng 2019)
of these clinical trials showed marginal effects with a trend towards decreasing mortality and adverse events. With
the reporting and publication of ongoing and completed randomized clinical trials on October 2019, an essential
need to re-evaluate and update current evidence elucidating the effect of tranexamic acid on clinical outcomes of
patients with traumatic brain injury becomes apparent.
Page 2 of 33
OBJECTIVES
The main objective of this systematic review will be to answer the research question “In patients with
traumatic brain injury (patient), does the administration of tranexamic acid (intervention) compared to placebo
(comparator) improves patients’ outcomes in terms of reduction head injury-related mortality, progression of brain
hemorrhage, need for neurosurgical intervention, and neurological function (outcome)?”
In general, this systematic review will evaluate the effect of tranexamic acid on clinical outcomes such as
head injury-related mortality, progression of brain hemorrhage, need for neurosurgical intervention, and functional
status upon discharge among patients with traumatic brain injury. Furthermore, this paper will also evaluate safety
outcomes of tranexamic acid such as development of vaso-occlusive events, seizures, and gastrointestinal bleeding
in the same among patients with traumatic brain injury.
METHODS
The systematic review and metanalysis will include publications of randomised controlled clinical trials
which utilized tranexamic acid in patients with traumatic brain injury.
The inclusion criteria of this study will be:
(A) Studies conducted in patients with traumatic brain injury
(B) Tranexamic acid administered intravenously at any dose during the admission
The exclusion criteria of this study will be:
(A) Preclinical studies, review articles, non-randomized controlled trials, case reports, and other publication types
that cannot provide complete information for clinical trials
Page 3 of 33
(B) Study population with other types of trauma (non-traumatic brain injury population)
(C) Duplication of study cohort from previous trials
The initial screening will be performed by two review investigators (CGM, FJMG) independently based on
the abstracts. For articles with relevant abstracts, the full-text versions will be obtained and will be assessed
independently based on the inclusion and exclusion criteria stated previously. No language restrictions will be
utilized in this study.
Types of studies
The review investigators will only include randomised controlled clinical trials, as this publication type is
considered to be the best study design for therapeutic investigations.
Types of study participants
Studies with patients with traumatic brain injury given tranexamic acid after admission will be included in
this analysis. On the other hand, patients with the following characteristics will be excluded in this analysis:
prehospital Glasgow Coma Scale of 3, estimated time from injury to hospital of more than two hours, unknown time
of injury, clinical suspicion by emergency medical service of seizures or history of seizures or myocardial infarction
or stroke, cardiopulmonary resuscitation initiated by emergency medical service, burns more than 20% of total body
surface area, suspected or known pregnancy, suspected or known prisoners, and prehospital tranexamic acid given
prior to randomization.
Types of interventions
Page 4 of 33
The review investigators plan to investigate the intravenous tranexamic acid (intervention) versus placebo
(control/comparator).
Types of outcome measures
Primary outcomes
The primary outcome measures to be investigated in this study will be traumatic brain injury-related
mortality, progression of brain hemorrhage, need for neurosurgical intervention, and functional status upon
discharge.
Secondary outcomes
The secondary outcome measures to be investigated in this study will be adverse events such as vaso-
occlusive events, new focal ischemic lesions, seizures, and gastrointestinal bleeding.
The review investigators will present a “Summary of findings table” reporting important clinical outcomes
listed according to priority.
Search methods for identification of studies
Electronic searches
The review investigators will systematically search the following main stream databases and sources
including The Cochrane Library, MEDLINE, and EMBASE from inception to 30 November 2019. The review
investigators will also search databases of ongoing trials including Clinical-Trials.gov (http://clinical trials.gov/),
meta Register of Controlled Trials (http://www.controlled-trials.com/mrct/), the EU Clinical Trials register (https://
www.clinical trialsregister.eu/) and the World Health Organization (WHO) International Clinical Trials Registry
Platform Search Portal (http://apps.who.int /trialsearch/).
Page 5 of 33
The systematic search will utilize the Medical Subject Headings (MeSH) terms for patients, “Brain Injuries,
Traumatic” [MeSH], “Brain Injuries” [MeSH], “Head Injuries, Closed” [MeSH], “Intracranial
Hemorrhage,” [MeSH] and for intervention, “Tranexamic acid,” [MeSH]. The manual search will utilize the same
terms in free text. The review investigators will continuously apply PubMed’s “My NCBI” (National Center for
Biotechnology Information) electronic mail alert service to identify newly published studies using a basic search
strategy. If the review investigators identify new studies for inclusion, the studies will be evaluated and findings will
be incorporated in the review before the submission of the final review draft. (Beller 2013).
If the review investigators find additional relevant key words during any of the electronic or other searches,
we will modify the electronic search strategies to incorporate these terms and document the changes. The review
investigators will place no restrictions on the language of publication when searching the electronic databases or
reviewing reference lists in identified studies.
Searching other resources
The review investigators will make attempts to identify other potentially eligible trials or ancillary
publications by searching the reference lists of retrieved included trials, (systematic) reviews, meta-analyses and
health technology assessment reports.
Data collection and analysis
Selection of studies
Two review investigators (CGM, FJMG) will independently scan the abstract, title, or both, of every
record retrieved, to determine which studies should be assessed further. The review investigators will investigate all
potentially relevant articles as full text. Disagreement will be resolved through consensus or recourse to a third
Page 6 of 33
review investigator (JMC). If resolving disagreement is not possible, the article will considered as “awaiting
assessment.” The review investigators will contact the study investigators for further clarifications. The review
investigators will present an adapted PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-
Analyses) flow-chart of study selection (Figure 1) (Liberati 2009).
Data extraction and management
For studies that fulfil inclusion criteria, two review investigators (CGM, FJMG) will independently extract
key participant and intervention characteristics and report data on clinical outcomes and adverse events using the
Cochrane Collaboration data extraction template, with any disagreements to be resolved by discussion, or if required
by a third investigator (JMC). The review investigators will provide information including trial identifier about
potentially-relevant ongoing studies in the table “Characteristics of ongoing studies” and in the appendix “Matrix
of study endpoints (trial documents)”. The review investigators will try to find the protocol of each included study,
either in databases of ongoing trials or in publications of study designs, or both, and specify the data in the appendix
“Matrix of study endpoints (protocol/trial documents)”.
Dealing with duplicate and companion publications
In the event of duplicate publications, companion documents or multiple reports of a primary study, the
review investigators will maximize yield of information by collating all available data and use the most complete
dataset aggregated across all known publications. In case of doubt the publication reporting the longest follow-up
associated with our primary or secondary outcomes will be given priority.
Assessment of risk of bias in included studies
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Two review investigators (CGM, FJMG) will assess the risk of bias of each included study independently.
Disagreements will be resolved by consensus, or by consultation with a third investigator (JMC). The review
investigators will assess risk of bias using the Cochrane Collaboration’s tool for assessment of risk of bias (Higgins
2011a;Higgins 2011b).We will assess the following criteria in this assessment:
(A) Random sequence generation (selection bias)
(B) Allocation concealment (selection bias)
(C) Blinding (performance bias and detection bias), blinding of participants and personnel assessed separately
from blinding of outcome assessment
(D) Incomplete outcome data (attrition bias)
(E) Selective reporting (reporting bias)
(F) Other bias
The review investigators will assess outcome reporting bias by integrating the results of “Examination of
outcome reporting bias” (Appendix 7), “Matrix of study endpoints (protocol/trial documents)” (Appendix 6) and
section “Outcomes (outcomes reported in abstract of publication)” of the “Characteristics of included studies”
section(Kirkham2010). This analysis will form the basis for the judgement of selective reporting (reporting bias).
The review investigators will judge “Risk of bias criteria” as “low risk”, “high risk” or “unclear risk” and
evaluate individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions
(Higgins 2011a). The review investigators will present a “Risk of bias” graph and a “Risk of bias summary” figure.
The review investigators will assess the impact of individual bias domains on study results at the endpoint
and study levels. For blinding of participants and personnel (performance bias), detection bias (blinding of outcome
assessors) and attrition bias (incomplete outcome data), the review investigators intend to evaluate risk of bias
Page 8 of 33
separately for subjective and objective outcomes (Hróbjartsson 2013). The review investigators will consider the
implications of missing outcome data from individual participants.
Measures of treatment effect
Dichotomous data will be expressed as risk ratios (RRs) with 95% confidence intervals (CIs). Continuous
data will be expressed in terms of mean differences (MD) with 95% CIs. Random-effects model will be utilized in
the
summarizing the treatment effects with dichotomous outcomes across studies.
Unit of analysis issues
The review investigators will take into account the level at which randomization occurred, such as cross-
over trials, cluster randomised trials and multiple observations for the same outcome.
Dealing with missing data
The review investigators will obtain missing data from study investigators, if feasible, and carefully
evaluate important numerical data such as screened, randomised participants as well as intention-to-treat and per-
protocol populations. The review investigators will investigate attrition rates, e.g. drop-outs, losses to follow up and
withdrawals, and critically appraise issues of missing data and imputation methods. Where standard deviations for
outcomes are not reported we will impute these values by assuming the standard deviation of the missing outcome to
be the average of the standard deviations from those studies where the information was reported. We will investigate
the impact of imputation on meta-analyses by means of sensitivity analysis.
Assessment of heterogeneity
Page 9 of 33
In the event of substantial clinical, methodological, or statistical heterogeneity, the review investigators will
not report study results as the pooled effect estimate in a metaanalysis. The review investigators will identify
heterogeneity by visual inspection of the forest plots and by using a standard Chi2 test with a significance level of α
= 0.1, in view of the low power of this test. The review investigators will examine heterogeneity using the I2
statistic, which quantifies inconsistency across studies, to assess the impact of heterogeneity on the meta-analysis
(Higgins 2002; Higgins 2003);an I2 statistic of more than 50% indicates a considerable level of inconsistency
(Higgins 2011a). When heterogeneity is found, the review investigators will attempt to determine potential reasons
for it by examining individual study and subgroup characteristics.
Assessment of reporting biases
If ten or more studies that investigate a particular outcome are found, the review investigators will utilize
funnel plots to assess small study effects. Owing to several possible explanations for funnel plot asymmetry, the
review investigators will interpret results carefully (Sterne 2011).
Data synthesis
Unless there is good evidence for homogeneous effects across studies, the review investigators will
summarize primarily low risk of bias data by means of a random-effects model (Wood 2008). The review
investigators will interpret random-effects meta-analyses with due consideration of the whole distribution of effects,
ideally by presenting a prediction interval (Higgins 2009). A prediction interval specifies a predicted range for the
true treatment effect in an individual study (Riley 2011). In addition, the review investigators will perform statistical
analyses according to the statistical guidelines contained in the latest version of the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2011a).
Subgroup analysis and investigation of heterogeneity
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The review investigators will carry out the subgroup analyses and plan to investigate interaction.
Sensitivity analysis
The review investigators will perform sensitivity analyses in order to explore the influence of the following
factors (when applicable) on effect sizes.
(A)Restricting the analysis to published studies.
(B)Restricting the analysis by taking into account risk of bias, as specified in the section “Assessment of risk of bias
in included studies.”
(C)Restricting the analysis to very long or large studies to establish the extent to which they dominate the results.
(D)Restricting the analysis to studies using the following filters: diagnostic criteria, imputation, language of
publication, source of funding (industry versus other), country.
The robustness of results will be tested by repeating the analysis using different measures of effect size (risk ratio
and odds ratio) and different statistical models (fixed-effect and random-effects models).
Ethical Considerations
In this systematic review and metaanalysis, no patient will be identified and no patient specific data will be
retrieved. Thus, privacy and confidentiality of the participants of included studies will not be violated. There will be
no direct involvement of research participants. As a metaanalysis, this study will entail no risk to the study
participants. The findings in this study may contribute to the current evidence in understanding the effect of
tranexamic acid on clinical outcomes of patients with traumatic brain injury. There will be no patient-related
compensations, reimbursement , and entitlements will be given for this study. As specific patients in the clinical
trials which will be included in this systematic review and metaanalysis will not be identified, informed consent will
not be obtained. There will be no recruitment of patients will be done in this study as well. The findings in this study
Page 11 of 33
will be made known to the general public and the scientific community through publication in print and electronic
forms and through presentations in the hospital and the academe. This study is initiated in the Department of
Emergency Medicine of the Philippine General Hospital. There will be no collaborative agreement between other
institutional and/or commercial entities will made in the planning, implementation, and dissemination of this study.
No study-related insurance will be utilized in this study. There are no conflicts-of-interests arising from financial,
familial, and proprietary considerations on all investigators or study sites. This study will be submitted to the
University of the Philippines Manila Research Ethics Board in compliance to the policy of research oversight and
ethical clearance.
Data Protection Plan
In this systematic review and metaanalysis, individual identities of all participants will not be recorded nor
disclosed to and by any of the investigators as outcome measures from randomized controlled trials (i.e. results in
terms of number of mortality cases, number of adverse events, etc.) will be the intended data to be collected and
analyzed. Identity of trial participants will be completely anonymized. No identifying records of trial participants
will be utilized in this study. Thus, privacy and confidentiality of all study participants will unconditionally be
protected. There will be no transcription nor translation of audio recordings from trial participants. Data in this
systematic review and metanalysis will be stored for five years or until future updates are intended to be performed.
Pooled data will be stored in electronic and print media. All three review investigators of this study will have access
to the all intended data.
Page 12 of 33
REFERENCES
Ayman 2018
Ayman E, Brijesh S, Asim M, Rifat L, Althani H. Efficacy of prehospital administration of tranexamic acid in
trauma patients: A meta-analysis of the randomized controlled trials. American Journal of Emergency Medicine.
2018;36(6):1079-87.
Beller 2013
Beller EM, Chen JK, Wang UL, Glasziou PP. Are systematic reviews up-to-date at the time of publication?.
Systematic Reviews 2013;2(1):36. [2046–4053: (Electronic)]
CDC 2019
Centers for Disease Control and Prevention. Surveillance report of traumatic brain injury-related emergency
department visits, hospitalizations, and deaths—United States, 2014. Centers for Disease Control and
Prevention, U.S. Department of Health and Human Services. Retrieved from https://www.cdc.gov/trauma
ticbraininjury/pdf/TBI-Surveillance-Report-FINAL_508.pdf on 10 October 2019
Consunji 2011
Consunji RJ, Serrato Marinas JP, Aspuria Maddumba JR, Dela Paz DA Jr. A profile of deaths among trauma
patients in a university hospital: the Philippine experience. J Inj Violence Res. 2011;3(2):85–89.
GBD 2016
GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators. Global, regional, and national burden
of traumatic brain injury and spinal cord injury, 1900-2016: A systematic analysis for the Global Burden of
Disease Study 2016. Lancet Neurol 2019;18(1):56–87.
Higgins 2002
Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 2002;21:1539–
58.
Higgins 2003
Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. BMJ
2003;327:557–60.
Higgins 2009
Higgins JPT, Thompson SG, Spiegelhalter DJ. A re-evaluation of random-effects meta-analysis. Journal of the
Royal Statistical Society: Series A (Statistics in Society) 2009; 172(1):137–59.
Higgins 2011a
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.
Higgins 2011b
Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool
for assessing risk of bias in randomised trials. BMJ 2011;343: d5928.
Hróbjartsson 2013
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Hróbjartsson A, Thomsen AS, Emanuelsson F, Tendal B, Hilden J, Boutron I, et al. Observer bias in randomized
clinical trials with measurement scale outcomes: a systematic review of trials with both blinded and nonblinded
assessors. Canadian Medical Association Journal 2013;185
(4):E201–11.
Kirkham 2010
Kirkham JJ, Dwan KM, Altman DG, Gamble C, Dodd S, Smyth R, et al. The impact of outcome reporting bias
in randomised controlled trials on a cohort of systematic reviews. BMJ 2010;340:c365. [DOI: 10.1136/
bmj.c365]
Liberati 2009
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for
reporting systematic and meta-analyses of studies that evaluate interventions: explanation and elaboration. PLoS
Medicine 2009;6(7):1–28. [DOI: 10.1371/journal.pmed.1000100]
Riley 2011
Riley RD, Higgins JP, Deeks JJ. Interpretation of random effects meta-analyses. BMJ 2011;342:d549.
Sterne 2011
Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and
interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011;343:d4002.
WHO 1998
Alberti KM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part
I: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabetic Medicine
1998;15:539–53.
Weng 2019
Weng S, Wang W, Wei Q, Lan H, Su J, Xu Y. Effect of tranexamic acid in patients with traumatic brain injury: A
systematic review and metaanalysis. World Neurosurg 2019;123:128-135.
Wood 2008
Wood L, Egger M, Gluud LL, Schulz KF, Juni P, Altman DG, et al. Empirical evidence of bias in treatment
effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ
2008;336 (7644):601–5.
Zehtabchi 2014
Zehtabchi S, Baki SGA, Falzon L, Nishijima DK,. Tranexamic acid for traumatic brain injury: A systematic
review and meta-analysis. Am J Emerg Med. 2014;32 (12):1503–9.
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FIGURE/S
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISM)
Study flow diagram
Page 16 of 33
APPENDICES
Appendix 1: Search Strategy
Search terms and databases
Unless otherwise stated, search terms are in free text terms.

Abbreviations:
“$”: stands for any character, “?” substitutes one or no character, adj: adjacent (i.e. number of words within range of search
term); exp: exploded MeSH; MeSH: medical subject heading (MEDLINE medical index term); pt: publication type; sh:
MeSH; tw: text word
The Cochrane Library
MEDLINE (PubMed)
EMBASE
“My NCBI” Alert Service (PubMed)
Other databases
Page 17 of 33
Page 18 of 33
Appendix 2: Description of Interventions
Interventions Comparator
Adequate interventiona Adequate comparatora
Characteristic [Route, Frequency, Total [Route, Frequency, Total
[Yes / No] [Yes / No]
dose] dose]
Study 1 Intervention Comparator
Footnotes
“-“ denotes not reported
aThe term “adequate” refers to sufficient use of the intervention or comparator with regard to dose, dose escalation, dosing scheme, provision
for contraindications, and other features necessary to establish a fair contrast between intervention and comparator
N: no; Y: yes
Appendix 3-4: Baseline characteristics (I)
Intervention and Duration of Participating

Characteristic Study period Country Setting
Comparator intervention population
Intervention
Study 1
Comparator
Footnotes
Intervention and Duration of Participating

Characteristic Study period Country Setting
Comparator intervention population
Intervention
Study 1
Comparator
Page 19 of 33
Footnotes
Page 20 of 33
Appendix 5: Matrix of study end points (Publications)
Endpoint reported in Endpoint not reported in

Study ID Characteristic Endpoint not measured
publication publication
Review’s Primary Outcomes
Adverse Events x
Example
Review’s Secondary Outcomes
Appendix 6: Matrix of study end points (Trial Documents)
Endpoint reported in Endpoint not reported in

Study ID Characteristic Endpoint not measured
publication publication
Review’s Primary Outcomes
Adverse Events x
Example
Review’s Secondary Outcomes
Page 21 of 33
x
Page 22 of 33
Appendix 7: Examination of outcome reporting bias
Clear that outcome was

Unclear whether the
Clear that outcome was measuredc [clear that
Clear that outcome was outcome was measuredd [not
measured and analyzeda outcome was measured but
measured and analyzedb mentioned but clinical
[trial report states that not necessarily analyzed
Study ID [trial report states that judgment says likely to have
outcome was analyzed but (judgment says likely to
outcome was analyzed but been measured and analyzed
only reports that result was have been analyzed but not
no results reported] but not reported on the basis
not significant] reported because of non-
of non-significant results]
significant results)]
Study 1
Footnotes
“High Risk of Bias” categories for outcome reporting bias according to the Outcome Reporting Bias in Trials (ORBIT) study classification
system of missing or incomplete outcome reporting in reports of randomised trials (Kirkham 2010).
aClassification “A” (Table 2, Kirkham 2010)
bClassification “A” (Table 2, Kirkham 2010)
cClassification “A” (Table 2, Kirkham 2010)
dClassification “A” (Table 2, Kirkham 2010)
Appendix 8: Definition of endpoint measurement (I)
Characteristic Endpoint 1 Endpoint 2 Endpoint 3 Endpoint 4 Endpoint 5 Endpoint 6
Study 1
Footnotes
ND: not defined; NI: not investigated
Appendix 9: Definition of endpoint measurement (II)
Study 1
Page 23 of 33
Footnotes
Page 24 of 33
Appendix 10: Definition of endpoint measurement (II)
Study 1
Footnotes
Appendix 11: Adverse Events (1)
Severe/ Severe/
Interventions
Randomized All adverse All adverse serios serios
Characteristic and Deaths [N] Deaths [%]
/ Safety [N] events [N] events [%] adverse adverse
comparator
events [N] events [%]
Intervention
Study 1
Placebo
Footnotes
Appendix 12: Adverse Events (1I)
Severe/ Severe/
Interventions
comparator
Intervention
Study 1
Placebo
Footnotes
Page 25 of 33
Page 26 of 33
Appendix 13: Adverse Events (1II)
Severe/ Severe/
Interventions
comparator
Intervention
Study 1
Placebo
Footnotes
Appendix 14: Adverse Events (IV)
Interventions and Randomized / Safety Specific Adverse Specific Adverse Specific Adverse
Characteristic comparators [N] Events [Description] Events [N] Events [%]
Intervention
Study 1 Placebo
All
Footnotes
Appendix 15: Survey of investigators providing additional information on included trials
Study author asked for

Characteristic Study author contacted Study author replied Study author provided data
additional information
Study 1 Y
Footnotes
N: no; Y: yes
Page 27 of 33
Page 28 of 33
Curriculum Vitae
Page 29 of 33
Surname: Manalo Name: Christopher
Position: Medical Officer IV Address: Block 178 Lot 06 Dahlia Street, Pembo,
Date of 1st Appointment: 01 Jan 2016 Makati City
Date of Latest Appointment: 01 Jan 2019 Contact No. 09178379374
Term of Office: Renewed Annually E-mail: cgmanalo@up.edu.ph
1. Education Master of Science in Epidemiology (Clinical Epidemiology)
College of Medicine, University of the Philippines Manila
Background Aug 2019-Present
1.1. Post- Residency Training in Emergency Medicine
graduate Department of Emergency Medicine, Philippine General Hospital
University of the Philippines Manila
degree 01 Jan 2016-31 Dec 2018
1.2. Graduate
Doctor of Medicine
degree Faculty of Medicine and Surgery, University of Santo Tomas
1.3. Bachelor’s 2009-2013
degree Bachelor of Science in Biology

1.4. Other Department of Biological Sciences, College of Science
University of Santo Tomas
qualificati 2005-2009
ons and
specializat
ions
2. Work
Experience Medical Officer IV
2.1. Present Department of Emergency Medicine, Philippine General Hospital
University of the Philippines Manila (01 Jan 2019-Present)
Work
Experienc Medical Officer III
Department of Emergency Medicine, Philippine General Hospital
e University of the Philippines Manila (01 Jan 2016-31 Dec 2018)
2.2. Previous
Work
Experienc
e
Page 30 of 33
3. Training/ Title of Training Date (dd/mm/ Venue Name of Training
yyyy) Provider
Workshops
Attended Metaanalysis 10/17/2019 Diamond Hotel, Manila Institute of Clinical
Workshop Epidemiology,
University of the
Philippines Manila
The Rizal Park Hotel,
Clinical Practice 09/11/2019-09/ Manila Institute of Clinical
Guideline 14/2019 Epidemiology,
Development for University of the
Technical Reviewers Philippines Manila
Preventing Research University of the

Misconduct 08/27/2019 Philippines Manila, University of the
Science & Technology Philippines Manila
Week
Research
Development of The Rizal Park Hotel,
Clinical Practice 08/15/2019-08/ Manila Institute of Clinical
Guidelines 16/2019 Epidemiology,
University of the
National Institute for Philippines Manila
Drug Abuse (NIDA) Philippine General
Clinical Trials 07/23/2019 Hospital Department of National Institute for
Network: Good Emergency Medicine – Drug Abuse (NIDA)
Clinical Practice Online Course Clinical Coordinating
Center
Training-Workshop
in Principles of Philippine General
Research Ethics and Hospital
Good Clinical 10/06/2017 Philippine General
Practice Hospital Expanded
Hospital Research
Emergency Office
Neurologic Life St. Luke’s College of
Support Medicine, Quezon City
06/16/2017 Neurocritical Care
06/17/2016 Society
UPMREB Review Panel

Member Signature
Date <dd/mm/yyyy>
Page 31 of 33
ESTIMATED BUDGETARY REQUIREMENTS
ITEMS AMOUNT
Office Supplies 5,00.00
Printing & Reproduction 5,00.00
Embase Subscription 40,000.00
Total Amount 50,000.00
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GAANT CHART
November December January February March April

2019 2019 2020 2020 2020 2020
Research
X
Protocol
Technical
X
Review
Ethics
X
Approval
Electronic
X
Search
Review of
Retrieved X X
Articles
Critical
Appraisal of
X X
Included
Studies
Analysis of
X X
Results
Final Paper X
Page 33 of 33

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Tranexamic Acid in Traumatic Brain Injury: A Systematic Review

and Metanalysis of Randomized Controlled Trials

placebo in traumatic brain injury.

Description of the condition

traumatic brain injury (CDC 2019).

traumatic brain injury (Zehtabchi 2013).

Description of the intervention

How the intervention might work

Why it is important to do this review

patients with traumatic brain injury becomes apparent.

hemorrhage, need for neurosurgical intervention, and neurological function (outcome)?”

in the same among patients with traumatic brain injury.

which utilized tranexamic acid in patients with traumatic brain injury.

The inclusion criteria of this study will be:

(A) Studies conducted in patients with traumatic brain injury

The exclusion criteria of this study will be:

that cannot provide complete information for clinical trials

(C) Duplication of study cohort from previous trials

utilized in this study.

considered to be the best study design for therapeutic investigations.

Types of study participants

Types of outcome measures

listed according to priority.

Search methods for identification of studies

Platform Search Portal (http://apps.who.int /trialsearch/).

reviewing reference lists in identified studies.

Searching other resources

health technology assessment reports.

Data collection and analysis

Analyses) flow-chart of study selection (Figure 1) (Liberati 2009).

Data extraction and management

“Matrix of study endpoints (protocol/trial documents)”.

Dealing with duplicate and companion publications

associated with our primary or secondary outcomes will be given priority.

Assessment of risk of bias in included studies

2011a;Higgins 2011b).We will assess the following criteria in this assessment:

(A) Random sequence generation (selection bias)

(B) Allocation concealment (selection bias)

from blinding of outcome assessment

(D) Incomplete outcome data (attrition bias)

(E) Selective reporting (reporting bias)

(F) Other bias

implications of missing outcome data from individual participants.

Measures of treatment effect

summarizing the treatment effects with dichotomous outcomes across studies.

Unit of analysis issues

Dealing with missing data

the impact of imputation on meta-analyses by means of sensitivity analysis.

for it by examining individual study and subgroup characteristics.

Assessment of reporting biases

review investigators will interpret results carefully (Sterne 2011).

Systematic Reviews of Interventions (Higgins 2011a).

Subgroup analysis and investigation of heterogeneity

factors (when applicable) on effect sizes.

(A)Restricting the analysis to published studies.

publication, source of funding (industry versus other), country.

Data Protection Plan

to the all intended data.

Appendix 1: Search Strategy

Search terms and databases

Unless otherwise stated, search terms are in free text terms.

The Cochrane Library

“My NCBI” Alert Service (PubMed)