Tranexamic acid for significant traumatic brain injury (The CRASH-3 trial): Statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial

Roberts, Ian; Belli, Antonio; Brenner, Amy; Chaudhri, Rizwana; Fawole, Bukola; Harris, Tim; Jooma, Rashid; Mahmood, Abda; Shokunbi, Temitayo; Shakur-Still, Haleema

doi:10.12688/wellcomeopenres.14700.1

Cited by 7 publications

(6 citation statements)

References 28 publications

(24 reference statements)

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“…Because most patients with TBI with a GCS score of 3 and those with bilateral unreactive pupils have a very poor prognosis regardless of treatment, their inclusion in the trial might bias any treatment effect towards the null. We therefore prespecified a sensitivity analysis that excluded these patients 11 . Cause of death was assessed by the responsible clinician.…”

Section: Methodsmentioning

confidence: 99%

“…However, we changed the primary outcome to head injury-related death in hospital within 28 days of injury in patients randomly assigned within 3 h of injury and limited recruitment to within 3 h of injury. We then increased the sample size to 13 000 to have approximately 10 000 patients treated within 3 h of injury 11 …”

Section: Methodsmentioning

confidence: 99%

“…Meta-analysis of these trials showed a reduction in mortality with tranexamic acid (risk ratio [RR] 0·63 [95% CI 0·40–0·99]) but provided no evidence about the effect of tranexamic acid on disability or adverse events. The CRASH-3 trial aimed to quantify the effects of tranexamic acid on head injury-related death, disability, and adverse events in patients with TBI 11 …”

Section: Introductionmentioning

confidence: 99%

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Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial

2019

The Lancet

637

255

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SummaryBackgroundTranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI.MethodsThis randomised, placebo-controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. This change was made blind to the trial data, in response to external evidence suggesting that delayed treatment is unlikely to be effective. We randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was head injury-related death in hospital within 28 days of injury in patients treated within 3 h of injury. We prespecified a sensitivity analysis that excluded patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline. All analyses were done by intention to treat. This trial was registered with ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14), and the Pan African Clinical Trial Registry (PACTR20121000441277).ResultsBetween July 20, 2012, and Jan 31, 2019, we randomly allocated 12 737 patients with TBI to receive tranexamic acid (6406 [50·3%] or placebo [6331 [49·7%], of whom 9202 (72·2%) patients were treated within 3 h of injury. Among patients treated within 3 h of injury, the risk of head injury-related death was 18·5% in the tranexamic acid group versus 19·8% in the placebo group (855 vs 892 events; risk ratio [RR] 0·94 [95% CI 0·86–1·02]). In the prespecified sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline, the risk of head injury-related death was 12·5% in the tranexamic acid group versus 14·0% in the placebo group (485 vs 525 events; RR 0·89 [95% CI 0·80–1·00]). The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64–0·95]) but not in patients with severe head injury (0·99 [95% CI 0·91–1·07]; p value for heterogeneity 0·030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0·005) but time to treatment had no obvious effect in patients with severe head injury (p=0·73). The risk of vascular occlusive events was similar in the tranexamic acid and placebo groups (RR 0·98 (0·74–1·28). The risk of seizures wa...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial

2019

The Lancet

637

255

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“…However it could help for exploring and generating hypothesis about mechanisms of pharmacological action by different statistical plan in the study patients. In my opinion, the analytical plan of CRASH3 trial and related studies 1 - 3 are comparable to the concept in meta analysis that exploring the clinical heterogeneity and statistical heterogeneity 4 - 5 among the studies of antifibrinolytic treatment for acute traumatic brain injury by the finding of reporting evidences. I look forward to seeing the result and encourage to continue such workings hereby.…”

mentioning

confidence: 82%

A nested randomised trial of the effect of tranexamic acid on intracranial haemorrhage and infarction in traumatic brain injury (CRASH-3 trial intracranial bleeding mechanistic study): Statistical analysis plan

Mahmood¹,

Roberts²,

Shakur-Still³

2019

Wellcome Open Res

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Background: The CRASH-3 trial is a randomised trial on the effect of tranexamic acid (TXA) versus placebo on death and disability in traumatic brain injury (TBI). The CRASH-3 intracranial bleeding mechanistic study (IBMS) is a randomised trial nested within the CRASH-3 trial to examine the effect of TXA versus placebo on intracranial bleeding and infarction. Methods: Patients eligible for the CRASH-3 trial, with a GCS of 12 or less or intracranial bleeding on a pre-randomisation CT scan are eligible for the IBMS. The occurrence of intracranial bleeding, infarction, haemorrhagic oedematous lesions, mass effect and haemorrhage evacuation is examined within 28 days of randomisation using routinely collected brain scans. The primary outcome is the volume of intra-parenchymal bleeding in patients randomised within three hours of injury (adjusted for prognostic covariates). Secondary outcomes include a composite “poor” outcome, progressive and new intracranial bleeding, intracranial bleeding after neurosurgery and cerebral infarcts seen up to 28 days post-randomisation. All outcomes will be compared between treatment groups. Statistical analyses: The primary outcome will be analysed using a covariate adjusted linear mixed model. The same analysis will be done separately for patients who undergo haemorrhage evacuation post-randomisation. We will express the effect of TXA on the composite outcome, new and progressive bleeding using relative risks and 95% CIs, and on cerebral infarcts using hazard ratios and 95% CIs. We will conduct sensitivity analyses assuming missing data are MCAR or MNAR. Conclusion: The IBMS will provide information on the mechanism of action of TXA in TBI. This pre-specified statistical analysis plan is a technical extension of the published protocol. Trial registration: The CRASH-3 trial was prospectively registered at the International Standard Randomised Controlled Trials registry (19 July 2011) and ClinicalTrials.gov (25 July 2011). The registries were updated with details for the IBMS on 20 December 2016.

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“…Following publication of the primary and secondary analyses detailed in the statistical analysis plan [ 25 ], individual de-identified patient data, including a data dictionary, will be made available via our data sharing portal, The Free Bank of Injury and Emergency Research Data (freeBIRD) website at https://ctu-app.lshtm.ac.uk/freebird/ .…”

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confidence: 99%

Accuracy of time to treatment estimates in the CRASH-3 clinical trial: impact on the trial results

Mansukhani

Frimley

Shakur-Still

et al. 2020

Trials

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Background Early treatment with tranexamic acid may reduce deaths after traumatic brain injury (TBI). In mild and moderate TBI, there is a time to treatment interaction, with early treatment being most beneficial. Time to treatment was recorded by clinicians and is subject to error. Using monitoring data from the CRASH-3 trial, we examine the impact of errors in time to treatment on estimated treatment effects. Methods The CRASH-3 trial was a randomised trial of the effect of tranexamic acid on death and vascular occlusive events in 12,737 TBI patients. This analysis includes the 8107 patients with a Glasgow coma scale score of 9 to 15 since previous analyses showed that these patients benefit most from early treatment. Clinician-recorded time to treatment was checked against ambulance and hospital records for 1368/12,737 (11%) patients. Patients who died were preferentially selected for monitoring and we monitored 36% of head injury deaths. We describe measurement errors using Bland-Altman graphs. We model the effect of tranexamic acid on head injury death using logistic regression with a time-treatment interaction term. We use regression calibration, multiple imputation and Bayesian analysis to estimate the impact of time to treatment errors. Results Clinicians rounded times to the nearest half or full hour in 66% of cases. Monitored times were also rounded and were identical to clinician times in 63% of patients. Times were underestimated by an average of 9 min (95% CI − 85, 66). There was more variability between clinician-recorded and monitored times in low- and middle-income countries than in high-income countries. The treatment effect estimate at 1 h was greater for monitored times OR = 0.61 (95% CI 0.47, 0.81) than for clinician-recorded times OR = 0.63 (95% CI 0.48, 0.83). All three adjustment methods gave similar time to treatment interactions. For Bayesian methods, the treatment effect at 1 h was OR = 0.58 (95% CI 0.43, 0.78). Using monitored times increased the time-treatment interaction term from 1.15 (95% CI 1.03, 1.27) to 1.16 (95% CI 1.05, 1.28). Conclusions Accurate estimation of time from injury to treatment is challenging, particularly in low resource settings. Adjustment for known errors in time to treatment had minimal impact on the trial results. Trial registration ClinicalTrials.gov NCT01402882 . Registered on 25 July 2011

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Tranexamic acid for significant traumatic brain injury (The CRASH-3 trial): Statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial

Cited by 7 publications

References 28 publications

Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial

Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial

A nested randomised trial of the effect of tranexamic acid on intracranial haemorrhage and infarction in traumatic brain injury (CRASH-3 trial intracranial bleeding mechanistic study): Statistical analysis plan

Accuracy of time to treatment estimates in the CRASH-3 clinical trial: impact on the trial results

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