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Statistical analysis plan for the Erythropoietin in Traumatic Brain Injury trial: a randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain injury.

ABSTRACT: BACKGROUND:The Erythropoietin in Traumatic Brain Injury (EPO-TBI) trial aims to determine whether the administration of erythropoietin to patients with moderate or severe traumatic brain injury improves patient-centred outcomes. METHODS:EPO-TBI is a multicentre, blinded, randomised, parallel groups, placebo-controlled, phase III superiority trial of erythropoietin in ICU patients with traumatic brain injury conducted in Australia and New Zealand, Saudi Arabia and Europe; 606 critically ill patients aged 15 to 65 years with moderate or severe acute traumatic brain injury will be enrolled. Trial patients will receive either 40,000 IU erythropoietin or placebo by subcutaneous injection administered weekly for up to three doses during their ICU admission. The primary outcome measure is the proportion of unfavourable neurological outcomes, comprising death or severe disability, observed at 6 months following randomisation utilizing the Extended Glasgow Outcome Scale. Secondary outcomes, also assessed at 6 months following randomisation, include the probability of an equal or greater Extended Glasgow Outcome Scale level, mortality, the proportions of patients with proximal deep venous thrombosis or with composite thrombotic vascular events, as well as assessment of quality of life and cost-effectiveness. The planned sample size will allow 90% power to detect a reduction from 50% to 36% in unfavourable neurological outcomes at a two-sided alpha of 0.05. DISCUSSION:A detailed analysis plan has been developed for EPO-TBI that is consistent with international guidelines. This plan specifies the statistical models for evaluation of primary and secondary outcomes, as well as defining covariates for adjusted analyses. Application of this statistical analysis plan to the forthcoming EPO-TBI trial will facilitate unbiased analyses of these important clinical data. TRIAL REGISTRATION:Australian New Zealand Clinical Trials Registry: ACTRN12609000827235 (22 September 2009). ClinicalTrials.gov: NCT00987454 (29 September 2009). European Drug Regulatory Authorities Clinical Trials: 2011-005235-22 (18 January 2012).

SUBMITTER: Presneill J

PROVIDER: S-EPMC4414377 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Statistical analysis plan for the Erythropoietin in Traumatic Brain Injury trial: a randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain injury.

Presneill Jeffrey J Little Lorraine L Nichol Alistair A French Craig C Cooper D James DJ Haddad Samir S Duranteau Jacques J Huet Olivier O Skrifvars Markus M Arabi Yaseen Y Bellomo Rinaldo R

Trials 20141220

<h4>Background</h4>The Erythropoietin in Traumatic Brain Injury (EPO-TBI) trial aims to determine whether the administration of erythropoietin to patients with moderate or severe traumatic brain injury improves patient-centred outcomes.<h4>Methods</h4>EPO-TBI is a multicentre, blinded, randomised, parallel groups, placebo-controlled, phase III superiority trial of erythropoietin in ICU patients with traumatic brain injury conducted in Australia and New Zealand, Saudi Arabia and Europe; 606 criti ...[more]

PMID: 25528574

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Project description:Background: Worldwide, traumatic brain injury (TBI) kills or hospitalises over 10 million people each year. Early intracranial bleeding is common after TBI, increasing the risk of death and disability. Tranexamic acid reduces blood loss in surgery and death due to bleeding in trauma patients with extra-cranial injury. Early administration of tranexamic acid in TBI patients might limit intracranial bleeding, reducing death and disability. The CRASH-3 trial aims to provide evidence on the effect of tranexamic acid on death and disability in TBI patients. We will randomly allocate about 13,000 TBI patients (approximately 10,000 within 3 hours of injury) to an intravenous infusion of tranexamic acid or matching placebo in addition to usual care. This paper presents a protocol update (version 2.1) and statistical analysis plan for the CRASH-3 trial. Results: The primary outcome is head injury death in hospital within 28 days of injury for patients treated within 3 hours of injury (deaths in patients treated after 3 hours will also be reported). Because there are reasons to expect that tranexamic acid will be most effective in patients treated immediately after injury and less effective with increasing delay, the effect in patients treated within one hour of injury is of particular interest. Secondary outcomes are all-cause and cause-specific mortality, vascular occlusive events, disability based on the Disability Rating Scale and measures suggested by patient representatives, seizures, neurosurgical intervention, neurosurgical blood loss, days in intensive care and adverse events. Sub-group analyses will examine the effect of tranexamic acid on head injury death stratified by time to treatment, severity of TBI and baseline risk. Conclusion: The CRASH-3 trial will provide reliable evidence of the effectiveness and safety of tranexamic acid in patients with acute TBI. Registration: International Standard Randomised Controlled Trials registry ( ISRCTN15088122) 19/07/2011, and ClinicalTrials.gov ( NCT01402882) 25/07/2011.

Project description:BACKGROUND:The Prophylactic hypOthermia to Lessen trAumatic bRain injury-Randomised Controlled Trial (POLAR-RCT) will evaluate whether early and sustained prophylactic hypothermia delivered to patients with severe traumatic brain injury improves patient-centred outcomes. METHODS:The POLAR-RCT is a multicentre, randomised, parallel group, phase III trial of early, prophylactic cooling in critically ill patients with severe traumatic brain injury, conducted in Australia, New Zealand, France, Switzerland, Saudi Arabia and Qatar. A total of 511 patients aged 18-60 years have been enrolled with severe acute traumatic brain injury. The trial intervention of early and sustained prophylactic hypothermia to 33 °C for 72 h will be compared to standard normothermia maintained at a core temperature of 37 °C. The primary outcome is the proportion of favourable neurological outcomes, comprising good recovery or moderate disability, observed at six months following randomisation utilising a midpoint dichotomisation of the Extended Glasgow Outcome Scale (GOSE). Secondary outcomes, also assessed at six months following randomisation, include the probability of an equal or greater GOSE level, mortality, the proportions of patients with haemorrhage or infection, as well as assessment of quality of life and health economic outcomes. The planned sample size will allow 80% power to detect a 30% relative risk increase from 50% to 65% (equivalent to a 15% absolute risk increase) in favourable neurological outcome at a two-sided alpha of 0.05. DISCUSSION:Consistent with international guidelines, a detailed and prospective analysis plan has been developed for the POLAR-RCT. This plan specifies the statistical models for evaluation of primary and secondary outcomes, as well as defining covariates for adjusted analyses and methods for exploratory analyses. Application of this statistical analysis plan to the forthcoming POLAR-RCT trial will facilitate unbiased analyses of these important clinical data. TRIAL REGISTRATION:ClinicalTrials.gov, NCT00987688 (first posted 1 October 2009); Australian New Zealand Clinical Trials Registry, ACTRN12609000764235 . Registered on 3 September 2009.

Project description:Traumatic brain injury is a leading cause of death and disability worldwide. Laboratory and clinical studies demonstrate a possible beneficial effect of erythropoietin in improving outcomes in the traumatic brain injury cohort. However, there are concerns regarding the association of erythropoietin and thrombosis in the critically ill. A large-scale, multi-centre, blinded, parallel-group, placebo-controlled, randomised trial is currently underway to address this hypothesis.The erythropoietin in traumatic brain injury trial is a stratified prospective, multi-centre, randomised, blinded, parallel-group, placebo-controlled phase III trial. It aims to determine whether the administration of erythropoietin compared to placebo improves neurological outcome in patients with moderate or severe traumatic brain injury at six months after injury. The trial is designed to recruit 606 patients between 15 and 65 years of age with severe (Glasgow Coma Score: 3 to 8) or moderate (Glasgow Coma Score: 9 to 12) traumatic brain injury in Australia, New Zealand, Kingdom of Saudi Arabia, France, Finland, Germany and Ireland. Trial patients will receive either subcutaneous erythropoietin or placebo within 24 hours of injury, and weekly thereafter for up to three doses during the intensive care unit admission. The primary outcome will be the combined proportion of unfavourable neurological outcomes at six months: severe disability or death. Secondary outcomes will include the rate of proximal deep venous thrombosis detected by compression Doppler ultrasound, six-month mortality, the proportion of patients with composite vascular events (deep venous thrombosis, pulmonary embolism, myocardial infarction, cardiac arrest and cerebrovascular events) at six months and quality of life with health economic evaluations.When completed, the trial aims to provide evidence on the efficacy and safety of erythropoietin in traumatic brain injury patients, and to provide clear guidance for clinicians in their management of this devastating condition.Australian New Zealand Clinical Trials registry: ACTRN12609000827235 (registered on 22 September 2009). Clinicaltrials.gov: NCT00987454 (registered on 29 September 2009). European Drug Regulatory Authorities Clinical Trials: 2011-005235-22 (registered on 18 January 2012).

Project description:ObjectivesTo conduct a feasibility randomised controlled trial of risperidone for the treatment of aggression in adults with traumatic brain injury (TBI).DesignMulticentre, parallel design, placebo controlled (1:1 ratio) double-blind feasibility trial with an embedded process evaluation. No statistical comparison was performed between the two study groups.SettingFour neuropsychiatric and neurology outpatient clinics in London and Kent, UK.ParticipantsOur aim was to recruit 50 patients with TBI over 18 months. Follow-up participants at 12 weeks using a battery of assessment scales to measure changes in aggressive behaviour and irritability (Modified Overt Aggression Scale (MOAS)-primary outcome, Irritability Questionnaire) as well as global functioning (Glasgow Outcome Scale-Extended, Clinical Global impression) and quality of life (EQ-5D-5L, SF-12), mental health (Hospital Anxiety and Depression Scale) and medication adverse effects (Udvalg for Kliniske Undersøgelser).ResultsSix participants were randomised to the active arm of the trial and eight to the placebo arm over a 10-month period (28% of our target). Two participants withdrew because of adverse events. Twelve out of 14 (85.7%) patients completed a follow-up assessment at 12 weeks. At follow-up, the scores of all outcome measures improved in both groups. Placebo group showed numerically better score change according to the primary outcome MOAS. No severe adverse events were reported. The overall rate of adverse events remained low. Data from the process evaluation suggest that existence of specialised TBI follow-up clinics, availability of a dedicated database of TBI patients' clinical details, simple study procedures and regular support to participants would enhance recruitment and retention in the trial. Feedback from participants showed that once in the study, they did not find the trial procedure onerous.ConclusionsIt was not feasible to conduct a successful randomised trial of risperidone versus placebo for post-TBI aggression using the methods we deployed in this study. It is not possible to draw any definitive conclusion about risperidone's efficacy from such a small trial.Trial registration numberISRCTN30191436.

Project description: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.

Project description:ObjectiveTo assess the effect of tranexamic acid (which reduces bleeding in surgical patients and reduces mortality due to bleeding in trauma patients) on intracranial haemorrhage in patients with traumatic brain injury.MethodsA nested, randomised, placebo controlled trial. All investigators were masked to treatment allocation. All analyses were by intention to treat. Patients 270 adult trauma patients with, or at risk of, significant extracranial bleeding within 8 hours of injury, who also had traumatic brain injury.InterventionsPatients randomly allocated to tranexamic acid (loading dose 1 g over 10 minutes, then infusion of 1 g over 8 hours) or matching placebo.Main outcome measuresIntracranial haemorrhage growth (measured by computed tomography) between hospital admission and then 24-48 hours later, with adjustment for Glasgow coma score, age, time from injury to the scans, and initial haemorrhage volume.ResultsOf the 133 patients allocated to tranexamic acid and 137 allocated to placebo, 123 (92%) and 126 (92%) respectively provided information on the primary outcome. All patients provided information on clinical outcomes. The mean total haemorrhage growth was 5.9 ml (SD 26.8) and 8.1 mL (SD 29.2) in the tranexamic acid and placebo groups respectively (adjusted difference -3.8 mL (95% confidence interval -11.5 to 3.9)). New focal cerebral ischaemic lesions occurred in 6 (5%) patients in the tranexamic acid group versus 12 (9%) in the placebo group (adjusted odds ratio 0.51 (95% confidence interval 0.18 to 1.44)). There were 14 (11%) deaths in the tranexamic acid group and 24 (18%) in the placebo group (adjusted odds ratio 0.47 (0.21 to 1.04)).ConclusionsThis trial shows that neither moderate benefits nor moderate harmful effects of tranexamic acid in patients with traumatic brain injury can be excluded. However, the analysis provides grounds for further clinical trials evaluating the effect of tranexamic acid in this population. Trial registration ISRCTN86750102.

Dataset Information

Statistical analysis plan for the Erythropoietin in Traumatic Brain Injury trial: a randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain injury.

Publications

Statistical analysis plan for the Erythropoietin in Traumatic Brain Injury trial: a randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain injury.

Similar Datasets

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