Edaravone for traumatic brain injury

  • Protocol
  • Intervention



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

To evaluate the efficacy and safety of edaravone for the treatment of TBI.


Traumatic brain injury (TBI) is a serious health problem worldwide (Abelson-Mitchell 2008). There are no known effective drugs for TBI despite decades of study on candidate agents for neuroprotection or improved recovery (Kelso 2011). TBI has a dynamic pathophysiology which evolves over time. In addition to primary brain damage, secondary brain damage caused by free radicals, inflammatory mediators and excitatory amino acids, may also aggravate the injury. Secondary brain damage can cause cerebral ischaemia, brain oedema and high intracranial pressure, which all lead to a high risk of death and disability (Ghajar 2000; Rosenfeld 2012). Edaravone, a novel free radical scavenger, is considered to be a potential therapy for TBI and may be effective and safe for TBI patients.

Description of the condition

Traumatic brain injury is defined as an acquired injury to the brain caused by an external physical force resulting in total or partial disability. It has become a leading cause of death and disability worldwide (Thornhill 2000; Whitnall 2006; Abelson-Mitchell 2008). Every year, approximately 50,000 people die and at least 5.3 million people live with long-term disabilities related to TBI in the United States (Binder 2005). The rates of incidence, fatality and disability are even higher in low- and middle-income countries (Hyder 2007).

TBI induces central nervous system degeneration and neuronal cell death through the initial mechanical insult and secondary damage, through ischaemia and oedema. Free radical production plays a key role in the secondary brain injury process (Dohi 2006). After TBI, the release of glutamate from neurons and the subsequent activation of glutamate receptors results in an increased Ca2+ influx into neuronal cells, which leads to the excessive production of free radicals. These free radicals can cause apoptotic cell death through lipid peroxidation and DNA damage in neuronal and glial cells (Tatsuki 2010). Therefore, scavenging the free radicals may be of great importance in the treatment of TBI. However, there is no precise evidence to support the use of any kind of free radical scavenger for TBI.

Description of the intervention

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a novel, potent free radical scavenger that has been shown to attenuate ischaemic and oedemic damage by reducing oxidative damage in a rat model of stroke (Nakamura 2008). The neuroprotective effect of edaravone in patients with stroke has been demonstrated and it is now widely used in China and Japan (Shinohara 2008; China 2010; Feng 2011; Yang 2011). O2- (superoxide radicals) and OH (hydroxyl radicals), as the reactive oxygen intermediates, are both important free radicals in vivo. Data from a rat model demonstrates that edaravone improves neurological impairment after TBI through inhibiting the production of O2- and OH (Tatsuki 2010). Edaravone has been evaluated and is increasingly being assessed by clinical researchers in vitro for TBI treatment (Dohi 2006; Lou 2006; Wang 2007; Chen 2009).

How the intervention might work

It has been demonstrated that there is a significant increase in free radicals after TBI, which play an important role in secondary brain injury (Bains 2012). Animal trials have shown that treatment with edaravone can efficiently increase neural stem cell numbers (Itoh 2009) and improve cerebral function (Tatsuki 2010) after TBI. By inhibiting the neuronal damage from free radicals, edaravone could reduce neurological impairment and improve the outcome of TBI patients (Dohi 2006).

Why it is important to do this review

Edaravone has been evaluated in a number of small, underpowered clinical trials. Its overall safety and efficacy in TBI patients is still uncertain. It is an expensive treatment, costing approximately USD 400 to 800 for one standard course of edaravone treatment per acute TBI patient in China (Wang 2007; Chen 2009; Simcere 2013). In order to provide the best evidence for clinical practice and further research on acute TBI, it is of great importance to systematically evaluate all trials of edaravone for acute TBI.


To evaluate the efficacy and safety of edaravone for the treatment of TBI.


Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs).

Types of participants

People with acute TBI. There will be no limitations on the participants' age, gender and severity of injury.

Types of interventions

Edaravone administered at any dose, duration and time post-injury.

  • Edaravone versus placebo

  • Edaravone plus routine treatment versus routine treatment alone

Types of outcome measures

Primary outcomes
  • Mortality

Secondary outcomes
  • Disability at final follow-up assessed by validated and reliable scales (such as the Glasgow Outcome Scale (GOS) or any other scale measuring disability)

  • Adverse effects of the drug (such as local infusion-related irritation, impairment of kidney or liver function, etc.)

The required information size is 1314, which will provide at least 90% power (α 0.05) to detect a 14% relative risk reduction in the primary outcome (mortality) with edaravone treatment compared with the standard treatment. This assumes that the proportional risk of the primary outcome will be reduced from 24% in the control group to 17% in the edaravone group.

Search methods for identification of studies

Searches will not be restricted by language or publication status.

Electronic searches

The Cochrane Injuries Group's Trials Search Co-ordinator will search the following electronic databases:

  1. Cochrane Injuries Group's Specialised Register (recent version);

  2. Cochrane Central Register of Controlled Trials (The Cochrane Library, recent 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 (1970 to present);

  6. ISI Web of Science: Conference Proceedings Citation Index-Science (1990 to present).

Searches will be based on the search strategy in Appendix 1, which was formulated in MEDLINE and will be adapted, as necessary, for the other databases.

Searching other resources

The authors will search the following ongoing trials registers:

We will also search the following Chinese information sources:

  • Chinese Biological Medicine Database (CBM-disc) (1863 to most recent date available);

  • China National Knowledge Infrastructure (CNKI) (1915 to most recent date available);

  • Chinese scientific periodical database of VIP INFORMATION (1989 to most recent date available);

  • Wanfang Data (1990 to most recent date available).

In an effort to identify further published, unpublished and ongoing trials, we will contact the pharmaceutical companies that manufacture edaravone.

Data collection and analysis

The Cochrane Injuries Group's Trials Search Coordinator will run the electronic database searches, collate the search results, remove duplicates, and pass the study references on to the authors for screening.

Selection of studies

Two review authors (Yukai Liu, Mahesh Roshan Jayavelu) will read the titles, abstracts and keywords of every record found. Articles will be eliminated if we can determine from the title and abstract that the article is not a report of a randomised controlled trial in humans or the trial does not address the effect of edaravone for TBI. The two review authors will read the full version of the resulting study reports and independently decide on their eligibility for inclusion in the review. Any discrepancy or disagreement will be discussed until a consensus is reached. If necessary, a third review author (Yingdong Zhang) will be consulted to resolve disagreements and we will note the differences in opinion in the full review.

Data extraction and management

Two review authors (Yukai Liu, Jie Yang) will extract data on study methods, patients, interventions, outcomes and results independently. We will extract the following data onto a standardised form.

  1. General information: published/unpublished study report, title, authors, reference/source, contact address, country, language of publication, year of publication, duplicate publications, sponsor, setting.

  2. Trial characteristics: design, duration of follow-up, method of randomisation, allocation concealment, blinding (patients, people administering treatment, people assessing outcome).

  3. Interventions: intervention (starting time, dose, route, frequency, duration), controlled intervention (dose, route, frequency, duration), co-medication(s) (dose, route, frequency, duration).

  4. Patients: inclusion/exclusion criteria, diagnostic criteria, total number and number in each group, age, baseline characteristics, similarity of groups at baseline (including any co-morbidity), assessment of compliance, withdrawals (reasons/description), subgroups.

  5. Outcomes: outcomes specified above, any other outcomes assessed, timing of outcome assessment, other events, length of follow-up, quality of reporting of outcomes.

The same two authors will check data extraction and input, and discuss any discrepancies. If necessary, the other authors will contribute to the discussion until consensus is reached. We will obtain any missing information in the article by contacting the authors through email or telephone. If the information remains unavailable, all of the authors will discuss and decide whether or not to include the trial in the review.

Assessment of risk of bias in included studies

Two authors (Jie Yang, Yukai Liu) will assess the following domains for each study independently according to The Cochrane Collaboration's 'Risk of bias' tool, which is described in Chapter 8 of theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreements will be discussed until a consensus reached and we will note differences in opinion in the full review. If necessary, a third review author (Yingdong Zhang) will be asked to make a final decision.

The domains of the 'Risk of bias' tool are as follows.

  • Sequence generation: was the allocation sequence adequately generated?

  • Allocation concealment: was allocation adequately concealed?

  • Blinding: was knowledge of the allocated interventions adequately prevented during the study?

  • Incomplete outcome data: were incomplete outcome data adequately addressed?

  • Selective outcome reporting: are reports of the study free of suggestion of selective outcome reporting?

  • Other potential sources of bias.

We will classify each domain above as 'high risk', 'low risk' or 'unclear risk' of bias. We will contact the authors of studies classified as 'unclear risk' for further information to facilitate a definitive decision.

Measures of treatment effect

We will make separate comparisons between edaravone and placebo, and edaravone plus routine treatment versus routine treatment. We will report results as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous data and as mean difference (MD) with 95% CI for continuous data.

Unit of analysis issues

A person is the unit of analysis. We do not anticipate encountering any unit of analysis issues.

Dealing with missing data

We will obtain any missing information by contacting study authors through email, mail or telephone. All of the review authors will discuss and decide whether or not to include a trial in the review if the information sought remains unavailable.

Assessment of heterogeneity

We will examine participants, interventions and outcomes for evidence of clinical heterogeneity. We plan to examine statistical heterogeneity with the I2 statistic and Chi2 test. We will consider statistically significant heterogeneity to be present when the P value of Chi2 is less than 0.05. Substantial heterogeneity will be considered to exist when the I2 value is more than 50%.

Assessment of reporting biases

We will create a funnel plot if 10 or more studies are included in the review and use this to detect publication and other biases.

Data synthesis

We will use the Cochrane Collaboration's 'Review Manager' software (RevMan 2012) to perform statistical analysis. We will employ a fixed-effect model when combining the results of individual studies.

Subgroup analysis and investigation of heterogeneity

We will compare the following domains in subgroup analyses:

  • severity of TBI (moderate TBI (Glasgow Coma Scale (GCS) 9 to 12) versus severe TBI (GCS ≤ 8));

  • the starting time of treatment (within 24 hours versus longer than 24 hours following the TBI);

  • dose of edaravone;

  • duration of edaravone treatment.

Sensitivity analysis

We will reanalyse the data excluding studies with inadequate or unclear allocation concealment.


We thank Ms Emma Sydenham (Managing Editor of the Cochrane Injuries Group), Deirdre Beecher and Karen Blackhall (Cochrane Injuries Group Trials Search Co-ordinators) for advice on writing the protocol.


Appendix 1. Search strategy

Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R)

1. exp Craniocerebral Trauma/
2. exp Brain Edema/
3. exp Glasgow Coma Scale/
4. exp Glasgow Outcome Scale/
5. exp Unconsciousness/
6. exp Cerebrovascular Trauma/
7. exp Pneumocephalus/
8. exp Epilepsy, post traumatic/
9. exp Cerebral hemorrhage, traumatic/
10. ((head or crani* or cerebr* or capitis or brain* or forebrain* or skull* or hemispher* or intra?cran* or inter?cran* or intracran* or intercran*) adj3 (injur* or trauma* or damag* or lesion* or wound* or destruction* or oedema* or edema* or contusion* or concus* or fracture*)).ab,ti.
11. ((head or crani* or cerebr* or brain* or intra?cran* or inter?cran* or intracran* or intercran*) adj3 (haematoma* or hematoma* or haemorrhag* or hemorrhag* or bleed* or pressur*)).ti,ab.
12. (Glasgow adj (coma or outcome) adj (scale* or score*)).ab,ti.
13. "rancho los amigos scale".ti,ab.
14. ("diffuse axonal injury" or "diffuse axonal injuries").ti,ab.
15. ((brain or cerebral or intracranial) adj3 (oedema or edema or swell*)).ab,ti.
16. ((unconscious* or coma* or concuss* or 'persistent vegetative state') adj3 (injur* or trauma* or damag* or wound* or fracture* or contusion* or haematoma* or hematoma* or haemorrhag* or hemorrhag* or pressur*)).ti,ab.
17. exp coma/
18. (injur* or trauma* or damag* or wound* or fractur* or contusion* or haematoma* or hematoma* or haemorrhag* or hemorrhag* or pressur* or lesion* or destruction* or oedema* or edema* or contusion* or concus*).ti,ab.
19. 17 and 18
20. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 19
21. Free Radical Scavengers/
22. edaravone.mp.
23. superoxide radicals.mp. or Superoxides/
24. hydroxyl radicals.mp. or Hydroxyl Radical/
25. MCI-186.mp.
26. 3-methyl-1-phenyl-2-pyrazolin-5-one.mp.
27. 21 or 22 or 23 or 24 or 25 or 26
28. 20 and 27
29. randomi?ed.ab,ti.
30. randomized controlled trial.pt.
31. controlled clinical trial.pt.
32. placebo.ab.
33. clinical trials as topic.sh.
34. randomly.ab.
35. trial.ti.
36. Comparative Study/
37. 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36
38. (animals not (humans and animals)).sh.
39. 37 not 38
40. 28 and 39

Contributions of authors

All authors contributed to writing the protocol.

Declarations of interest

None known.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Nanjing Health Bureau Youth Talent Project, China.

    The work was supported by the Project Grant from the Nanjing Health Bureau Youth Talent Project. The study was designed, conducted, analyzed and interpreted by the investigators independent of sponsors.