scholarly journals Statistical analysis plan: Early mobilization by head-up tilt with stepping versus standard care after severe traumatic brain injury

2021 ◽  
pp. 100856
Author(s):  
Christian Gunge Riberholt ◽  
Christian Gluud ◽  
Janus Christian Jakobsen ◽  
Christian Ovesen ◽  
Jesper Mehlsen ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Statistical Analysis ◽  
Brain Injury ◽  
Severe Traumatic Brain Injury ◽  
Standard Care ◽  
Early Mobilization ◽  
Statistical Analysis Plan ◽  
Head Up Tilt

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 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 ◽  
Jesper Mehlsen ◽  
Kirsten Møller
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 the data collected in the randomised clinical feasibility trial for early mobilisation by head-up tilt with stepping versus standard care after severe traumatic brain injury. The primary feasibility outcomes are the proportion of included participants who were randomised compared with 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, the coma recovery scale – revised, the early functional ability scale, and the functional independence measure. Explorative physiological outcomes are electrocardiography, mean arterial pressure, 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 continuous electrocardiographic heart rate was measured. 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 be used for deciding to launch and designing a larger multicentre randomised clinical trial. Trial registration: ClinicalTrials.gov identifier: NCT02924649. Registered on 3 October 2016.

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 prospective, randomized Phase II clinical trial to evaluate the effect of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury

2013 ◽  
Vol 118 (6) ◽  
pp. 1317-1328 ◽  
Author(s):  
Sarah B. Rockswold ◽  
Gaylan L. Rockswold ◽  
David A. Zaun ◽  
Jiannong Liu
Keyword(s):  
Clinical Trial ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Intracranial Pressure ◽  
Clinical Outcome ◽  
Severe Traumatic Brain Injury ◽  
Standard Care ◽  
Cerebral Metabolism ◽  
Control Group ◽  
Normobaric Hyperoxia

Object Preclinical and clinical investigations indicate that the positive effect of hyperbaric oxygen (HBO2) for severe traumatic brain injury (TBI) occurs after rather than during treatment. The brain appears better able to use baseline O2 levels following HBO2 treatments. In this study, the authors evaluate the combination of HBO2 and normobaric hyperoxia (NBH) as a single treatment. Methods Forty-two patients who sustained severe TBI (mean Glasgow Coma Scale [GCS] score 5.7) were prospectively randomized within 24 hours of injury to either: 1) combined HBO2/NBH (60 minutes of HBO2 at 1.5 atmospheres absolute [ATA] followed by NBH, 3 hours of 100% fraction of inspired oxygen [FiO2] at 1.0 ATA) or 2) control, standard care. Treatments occurred once every 24 hours for 3 consecutive days. Intracranial pressure, surrogate markers for cerebral metabolism, and O2 toxicity were monitored. Clinical outcome was assessed at 6 months using the sliding dichotomized Glasgow Outcome Scale (GOS) score. Mixed-effects linear modeling was used to statistically test differences between the treatment and control groups. Functional outcome and mortality rates were compared using chi-square tests. Results There were no significant differences in demographic characteristics between the 2 groups. In comparison with values in the control group, brain tissue partial pressure of O2 (PO2) levels were significantly increased during and following combined HBO2/NBH treatments in both the noninjured and pericontusional brain (p < 0.0001). Microdialysate lactate/pyruvate ratios were significantly decreased in the noninjured brain in the combined HBO2/NBH group as compared with controls (p < 0.0078). The combined HBO2/NBH group's intracranial pressure values were significantly lower than those of the control group during treatment, and the improvement continued until the next treatment session (p < 0.0006). The combined HBO2/NBH group's levels of microdialysate glycerol were significantly lower than those of the control group in both noninjured and pericontusional brain (p < 0.001). The combined HBO2/NBH group's level of CSF F2-isoprostane was decreased at 6 hours after treatment as compared with that of controls, but the difference did not quite reach statistical significance (p = 0.0692). There was an absolute 26% reduction in mortality for the combined HBO2/NBH group (p = 0.048) and an absolute 36% improvement in favorable outcome using the sliding dichotomized GOS (p = 0.024) as compared with the control group. Conclusions In this Phase II clinical trial, in comparison with standard care (control treatment) combined HBO2/NBH treatments significantly improved markers of oxidative metabolism in relatively uninjured brain as well as pericontusional tissue, reduced intracranial hypertension, and demonstrated improvement in markers of cerebral toxicity. There was significant reduction in mortality and improved favorable outcome as measured by GOS. The combination of HBO2 and NBH therapy appears to have potential therapeutic efficacy as compared with the 2 treatments in isolation. Clinical trial registration no.: NCT00170352 (ClinicalTrials.gov).

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 Early Orthostatic Exercise by Head-Up Tilt With Stepping vs. Standard Care After Severe Traumatic Brain Injury Is Feasible

2021 ◽  
Vol 12 ◽  
Author(s):  
Christian Gunge Riberholt ◽  
Markus Harboe Olsen ◽  
Christian Baastrup Søndergaard ◽  
Christian Gluud ◽  
Christian Ovesen ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Adverse Events ◽  
Severe Traumatic Brain Injury ◽  
Standard Care ◽  
Randomized Clinical Trials ◽  
Neurointensive Care ◽  
Control Group ◽  
Neurointensive Care Unit

Background: Intensive rehabilitation of patients after severe traumatic brain injury aims to improve functional outcome. The effect of initiating rehabilitation in the early phase, in the form of head-up mobilization, is unclear.Objective: To assess whether early mobilization is feasible and safe in patients with traumatic brain injury admitted to a neurointensive care unit.Methods: This was a randomized parallel-group clinical trial, including patients with severe traumatic brain injury (Glasgow coma scale &lt;11 and admission to the neurointensive care unit). The intervention consisted of daily mobilization on a tilt-table for 4 weeks. The control group received standard care. Outcomes were the number of included participants relative to all patients with traumatic brain injury who were approached for inclusion, the number of conducted mobilization sessions relative to all planned sessions, as well as adverse events and reactions. Information on clinical outcome was collected for exploratory purposes.Results: Thirty-eight participants were included (19 in each group), corresponding to 76% of all approached patients [95% confidence interval (CI) 63–86%]. In the intervention group, 74% [95% CI 52–89%] of planned sessions were carried out. There was no difference in the number of adverse events, serious adverse events, or adverse reactions between the groups.Conclusions: Early head-up mobilization is feasible in patients with severe traumatic brain injury. Larger randomized clinical trials are needed to explore potential benefits and harms of such an intervention.Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT02924649]. Registered on 3rd October 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.

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