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.
Types of outcome measures
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.
The Cochrane Injuries Group's Trials Search Co-ordinator will search the following electronic databases:
Cochrane Injuries Group's Specialised Register (recent version);
Cochrane Central Register of Controlled Trials (The Cochrane Library, recent issue);
Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R) (1946 to present);
EMBASE Classic + EMBASE (OvidSP) (1947 to present);
ISI Web of Science: Science Citation Index Expanded (1970 to present);
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In an effort to identify further published, unpublished and ongoing trials, we will contact the pharmaceutical companies that manufacture edaravone.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.
General information: published/unpublished study report, title, authors, reference/source, contact address, country, language of publication, year of publication, duplicate publications, sponsor, setting.
Trial characteristics: design, duration of follow-up, method of randomisation, allocation concealment, blinding (patients, people administering treatment, people assessing outcome).
Interventions: intervention (starting time, dose, route, frequency, duration), controlled intervention (dose, route, frequency, duration), co-medication(s) (dose, route, frequency, duration).
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.
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.
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.
We will reanalyse the data excluding studies with inadequate or unclear allocation concealment.