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

2018 ◽  
Vol 3 ◽  
pp. 86 ◽  
Author(s):  
Ian Roberts ◽  
Antonio Belli ◽  
Amy Brenner ◽  
Rizwana Chaudhri ◽  
Bukola Fawole ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Statistical Analysis ◽  
Brain Injury ◽  
Head Injury ◽  
Blood Loss ◽  
Tranexamic Acid ◽  
Statistical Analysis Plan ◽  
Intracranial Bleeding ◽  
Injury Death ◽  
Risk Of Death

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.

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

2018 ◽  
Vol 3 ◽  
pp. 86 ◽  
Author(s):  
Ian Roberts ◽  
Antonio Belli ◽  
Amy Brenner ◽  
Rizwana Chaudhri ◽  
Bukola Fawole ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Statistical Analysis ◽  
Brain Injury ◽  
Head Injury ◽  
Blood Loss ◽  
Tranexamic Acid ◽  
Statistical Analysis Plan ◽  
Intracranial Bleeding ◽  
Injury Death ◽  
Reliable Evidence

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 reliable evidence on the effect of tranexamic acid on death and disability in TBI patients. We will randomly allocate about 13,000 TBI patients 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 strong scientific 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 (myocardial infarction, pulmonary embolism, deep vein thrombosis, stroke), 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.

scholarly journals 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

2019 ◽  
Vol 3 ◽  
pp. 99
Author(s):  
Abda Mahmood ◽  
Ian Roberts ◽  
Haleema Shakur-Still
Keyword(s):  
Traumatic Brain Injury ◽  
Statistical Analysis ◽  
Brain Injury ◽  
Primary Outcome ◽  
Randomised Trial ◽  
Statistical Analysis Plan ◽  
Intracranial Bleeding ◽  
Mechanistic Study ◽  
Cerebral Infarcts ◽  
Post Randomisation

Background: The CRASH-3 trial is a randomised trial on the effect of tranexamic acid (TXA) 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 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.

scholarly journals 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

2018 ◽  
Vol 3 ◽  
pp. 99 ◽  
Author(s):  
Abda Mahmood ◽  
Ian Roberts ◽  
Haleema Shakur-Still
Keyword(s):  
Traumatic Brain Injury ◽  
Statistical Analysis ◽  
Brain Injury ◽  
Primary Outcome ◽  
Randomised Trial ◽  
Statistical Analysis Plan ◽  
Intracranial Bleeding ◽  
Mechanistic Study ◽  
Cerebral Infarcts ◽  
Post Randomisation

Background: The CRASH-3 trial is a randomised trial on the effect of tranexamic acid (TXA) 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 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 intracranial bleeding in patients randomised within three hours of injury (adjusted for prognostic covariates). Secondary outcomes include progressive and new intracranial bleeding, intracranial bleeding after neurosurgery and new cerebral infarcts up to 28 days post-randomisation. All outcomes will be compared between treatment groups. Statistical analyses: The primary outcome will be analysed using absolute measures (ANCOVA) and relative measures (ratios). The same analysis will be done separately for patients who undergo haemorrhage evacuation post-randomisation. We will express the effect of TXA on new and progressive bleeding using relative risks and 95% CIs, and on cerebral infarcts using hazard ratios and 95% CIs. If any missing post-randomisation scans appear to be missing not at random, we will conduct sensitivity analyses to explore the implications. 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.

scholarly journals Tranexamic acid to reduce head injury death in people with traumatic brain injury: the CRASH-3 international RCT

2021 ◽  
Vol 25 (26) ◽  
pp. 1-76
Author(s):  
Ian Roberts ◽  
Haleema Shakur-Still ◽  
Amy Aeron-Thomas ◽  
Danielle Beaumont ◽  
Antonio Belli ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Head Injury ◽  
Confidence Interval ◽  
Tranexamic Acid ◽  
Risk Ratio ◽  
Group Versus ◽  
Acid Group ◽  
Injury Death ◽  
Moderate Traumatic Brain Injury

Background Tranexamic acid safely reduces mortality in traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury and can cause brain herniation and death. We assessed the effects of tranexamic acid in traumatic brain injury patients. Objective To assess the effects of tranexamic acid on death, disability and vascular occlusive events in traumatic brain injury patients. We also assessed cost-effectiveness. Design Randomised trial and economic evaluation. 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. All analyses were by intention to treat. We assessed the cost-effectiveness of tranexamic acid versus no treatment from a UK NHS perspective using the trial results and a Markov model. Setting 175 hospitals in 29 countries. Participants Adults with traumatic brain injury within 3 hours of injury with a Glasgow Coma Scale score of ≤ 12 or any intracranial bleeding on computerised tomography scan, and no major extracranial bleeding, were eligible. Intervention Tranexamic acid (loading dose 1 g over 10 minutes then infusion of 1 g over 8 hours) or matching placebo. Main outcome measures Head injury death in hospital within 28 days of injury in patients treated within 3 hours of injury. Secondary outcomes were early head injury deaths, all-cause and cause-specific mortality, disability, vascular occlusive events, seizures, complications and adverse events. Results Among patients treated within 3 hours of injury (n = 9127), the risk of head injury death was 18.5% in the tranexamic acid group versus 19.8% in the placebo group (855/4613 vs. 892/4514; risk ratio 0.94, 95% confidence interval 0.86 to 1.02). In a prespecified analysis excluding patients with a Glasgow Coma Scale score of 3 or bilateral unreactive pupils at baseline, the results were 12.5% in the tranexamic acid group versus 14.0% in the placebo group (485/3880 vs. 525/3757; risk ratio 0.89, 95% confidence interval 0.80 to 1.00). There was a reduction in the risk of head injury death with tranexamic acid in those with mild to moderate head injury (166/2846 vs. 207/2769; risk ratio 0.78, 95% confidence interval 0.64 to 0.95), but in those with severe head injury (689/1739 vs. 685/1710; risk ratio 0.99, 95% confidence interval 0.91 to 1.07) there was no apparent reduction (p-value for heterogeneity = 0.030). Early treatment was more effective in mild and moderate head injury (p = 0.005), but there was no obvious impact of time to treatment in cases of severe head injury (p = 0.73). The risk of disability, vascular occlusive events and seizures was similar in both groups. Tranexamic acid is highly cost-effective for mild and moderate traumatic brain injury (base case of £4288 per quality-adjusted life-year gained). Conclusion Early tranexamic acid treatment reduces head injury deaths. Treatment is cost-effective for patients with mild or moderate traumatic brain injury, or those with both pupils reactive. Future work Further trials should examine early tranexamic acid treatment in mild head injury. Research on alternative routes of administration is needed. Limitations Time to treatment may have been underestimated. Trial registration Current Controlled Trials ISRCTN15088122, ClinicalTrials.gov NCT01402882, EudraCT 2011-003669-14, Pan African Clinical Trial Registry PACTR20121000441277. Funding The project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 26. See the NIHR Journals Library website for further project information. In addition, funding was provided by JP Moulton Charitable Trust, Joint Global Health Trials (Medical Research Council, Department for International Development and the Wellcome Trust). This project was funded by the NIHR Global Health Trials programme.

scholarly journals 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

2019 ◽  
Vol 3 ◽  
pp. 99
Author(s):  
Abda Mahmood ◽  
Ian Roberts ◽  
Haleema Shakur-Still
Keyword(s):  
Traumatic Brain Injury ◽  
Statistical Analysis ◽  
Brain Injury ◽  
Primary Outcome ◽  
Randomised Trial ◽  
Statistical Analysis Plan ◽  
Intracranial Bleeding ◽  
Mechanistic Study ◽  
Cerebral Infarcts ◽  
Post Randomisation

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.

scholarly journals Statistical analysis plan for Early mobilisation by head-up tilt with stepping versus standard care after severe traumatic brain injury – a randomised clinical feasibility trial

2019 ◽  
Author(s):  
Christian Gunge Riberholt ◽  
Christian Gluud ◽  
Janus Christian Jakobsen ◽  
Christian Ovesen ◽  
Jesper Mehlsen ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Statistical Analysis ◽  
Brain Injury ◽  
Standard Care ◽  
Statistical Analysis Plan ◽  
Feasibility Trial ◽  
Tilt Test ◽  
Early Mobilisation ◽  
Head Up Tilt ◽  
Head Up Tilt Test

Abstract Background: Early mobilisation on a tilt table with stepping versus standard care may be beneficial for patients with severe brain injury, but data from randomised clinical trials are lacking. Methods: This statistical analysis plan describes the analyses of data collected in a randomised clinical feasibility trial for early mobilisation by head-up tilt with stepping versus standard care after severe traumatic brain injury. Primary feasibility outcomes are the proportion of included participants who were randomised out of all screened patients; the proportion of participants allocated to the experimental intervention who received at least 60% of the planned exercise sessions; and safety outcomes such as severe adverse events and reactions and adverse events and reactions. Exploratory clinical outcomes are suspected unexpected severe adverse reactions; and functional outcomes as assessed by Coma Recovery Scale – Revised at four weeks; Early Functional Ability Scale, and Functional Independence Measure at three months. Exploratory physiological outcomes are electrocardiographic data; mean arterial pressure; and middle cerebral artery blood flow velocity, all obtained during the head-up tilt test. From the first head-up tilt test and five days onwards, a heart rate was measured by continuous electrocardiography. The detailed description includes the statistical analysis including use of multiple imputation and Trial Sequential Analysis. Conclusions: The present statistical analysis plan serves to minimise potential trial reporting bias and selective P hacking and to improve transparency. This feasibility trial will inform design and eventual launching of a larger multicentre randomised clinical trial. Trial registration: ClinicalTrials.gov identifier: NCT02924649. Registered on 3 October 2016.

scholarly journals Statistical analysis plan for early mobilisation by head-up tilt with stepping versus standard care after severe traumatic brain injury – a randomised clinical feasibility trial

2019 ◽  
Author(s):  
Christian Gunge Riberholt ◽  
Christian Gluud ◽  
Janus Christian Jakobsen ◽  
Christian Ovesen ◽  
Jesper Mehlsen ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Statistical Analysis ◽  
Brain Injury ◽  
Adverse Events ◽  
Severe Traumatic Brain Injury ◽  
Standard Care ◽  
Statistical Analysis Plan ◽  
Feasibility Trial ◽  
Early Mobilisation ◽  
Head Up Tilt

Abstract Background: Early mobilisation on a tilt table with stepping versus standard care may be beneficial for patients with severe brain injury, but data from randomised clinical trials are lacking. Methods: This detailed statistical analysis plan describes the analyses of data collected in a randomised clinical feasibility trial for early mobilisation by head-up tilt with stepping versus standard care after severe traumatic brain injury. Primary feasibility outcomes are the proportion of included participants who were randomised out of all screened patients; the proportion of participants allocated to the experimental intervention who received at least 60% of the planned exercise sessions; and safety outcomes such as adverse events and reactions and serious adverse events and reactions. Exploratory clinical outcomes are suspected unexpected serious adverse reactions; and functional outcomes as assessed by Coma Recovery Scale – Revised at four weeks; Early Functional Ability Scale and Functional Independence Measure at three months. The description includes the statistical analyses including use of multiple imputation and Trial Sequential Analysis. Conclusions: The present statistical analysis plan serves to minimise potential trial reporting bias and selective P hacking and to improve transparency. This trial will inform the feasibility of a potential future multicentre randomised clinical trial. Trial registration: ClinicalTrials.gov identifier: NCT02924649. Registered on 3 October 2016.

scholarly journals Effect of tranexamic acid on intracranial haemorrhage and infarction in patients with traumatic brain injury: a pre-planned substudy in a sample of CRASH-3 trial patients

2020 ◽  
pp. emermed-2020-210424
Author(s):  
Abda Mahmood ◽  
Kelly Needham ◽  
Haleema Shakur-Still ◽  
Tim Harris ◽  
Sabariah Faizah Jamaluddin ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Clinical Practice ◽  
Brain Injury ◽  
Head Injury ◽  
Tranexamic Acid ◽  
Intracranial Haemorrhage ◽  
Routine Clinical Practice ◽  
Intraparenchymal Haemorrhage ◽  
Scan Data ◽  
Post Randomisation

BackgroundEarly tranexamic acid (TXA) treatment reduces head injury deaths after traumatic brain injury (TBI). We used brain scans that were acquired as part of the routine clinical practice during the CRASH-3 trial (before unblinding) to examine the mechanism of action of TXA in TBI. Specifically, we explored the potential effects of TXA on intracranial haemorrhage and infarction.MethodsThis is a prospective substudy nested within the CRASH-3 trial, a randomised placebo-controlled trial of TXA (loading dose 1 g over 10 min, then 1 g infusion over 8 hours) in patients with isolated head injury. CRASH-3 trial patients were recruited between July 2012 and January 2019. Participants in the current substudy were a subset of trial patients enrolled at 10 hospitals in the UK and 4 in Malaysia, who had at least one CT head scan performed as part of the routine clinical practice within 28 days of randomisation. The primary outcome was the volume of intraparenchymal haemorrhage (ie, contusion) measured on a CT scan done after randomisation. Secondary outcomes were progressive intracranial haemorrhage (post-randomisation CT shows >25% of volume seen on pre-randomisation CT), new intracranial haemorrhage (any haemorrhage seen on post-randomisation CT but not on pre-randomisation CT), cerebral infarction (any infarction seen on any type of brain scan done post-randomisation, excluding infarction seen pre-randomisation) and intracranial haemorrhage volume (intraparenchymal + intraventricular + subdural + epidural) in those who underwent neurosurgical haemorrhage evacuation. We planned to conduct sensitivity analyses excluding patients who were severely injured at baseline. Dichotomous outcomes were analysed using relative risks (RR) or hazard ratios (HR), and continuous outcomes using a linear mixed model.Results1767 patients were included in this substudy. One-third of the patients had a baseline GCS (Glasgow Coma Score) of 3 (n=579) and 24% had unilateral or bilateral unreactive pupils. 46% of patients were scanned pre-randomisation and post-randomisation (n=812/1767), 19% were scanned only pre-randomisation (n=341/1767) and 35% were scanned only post-randomisation (n=614/1767). In all patients, there was no evidence that TXA prevents intraparenchymal haemorrhage expansion (estimate=1.09, 95% CI 0.81 to 1.45) or intracranial haemorrhage expansion in patients who underwent neurosurgical haemorrhage evacuation (n=363) (estimate=0.79, 95% CI 0.57 to 1.11). In patients scanned pre-randomisation and post-randomisation (n=812), there was no evidence that TXA reduces progressive haemorrhage (adjusted RR=0.91, 95% CI 0.74 to 1.13) and new haemorrhage (adjusted RR=0.85, 95% CI 0.72 to 1.01). When patients with unreactive pupils at baseline were excluded, there was evidence that TXA prevents new haemorrhage (adjusted RR=0.80, 95% CI 0.66 to 0.98). In patients scanned post-randomisation (n=1431), there was no evidence of an increase in infarction with TXA (adjusted HR=1.28, 95% CI 0.93 to 1.76). A larger proportion of patients without (vs with) a post-randomisation scan died from head injury (38% vs 19%: RR=1.97, 95% CI 1.66 to 2.34, p<0.0001).ConclusionTXA may prevent new haemorrhage in patients with reactive pupils at baseline. This is consistent with the results of the CRASH-3 trial which found that TXA reduced head injury death in patients with at least one reactive pupil at baseline. However, the large number of patients without post-randomisation scans and the possibility that the availability of scan data depends on whether a patient received TXA, challenges the validity of inferences made using routinely collected scan data. This study highlights the limitations of using routinely collected scan data to examine the effects of TBI treatments.Trial registration numberISRCTN15088122.

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