{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:11:17Z","timestamp":1772169077573,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.17421.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T00:00:00Z","timestamp":1730073600000}},{"DOI":"10.12688\/wellcomeopenres.17421.2","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T00:00:00Z","timestamp":1730073600000}}],"reference-count":28,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T00:00:00Z","timestamp":1730073600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department for International Development"},{"name":"JP Moulton Charitable Trust"},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["105439"],"award-info":[{"award-number":["105439"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["MRM0092111"],"award-info":[{"award-number":["MRM0092111"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100016270","name":"Global Challenges Research Fund","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100016270","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000276","name":"Department of Health and Social Care","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000276","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Medical Research Council"},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"crossref","award":["NIHR HTA; 14\/190\/01"],"award-info":[{"award-number":["NIHR HTA; 14\/190\/01"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns3:p>Background Each year world-wide about 65 million people sustain a mild traumatic brain injury (mTBI). Fatigue is a common and distressing symptom after mTBI. We examine the effect of tranexamic acid (TXA) on fatigue in patients with mTBI using data from the CRASH-3 trial. Methods The CRASH-3 trial randomised 9,202 patients with traumatic brain injury and no significant extracranial bleeding to receive TXA or placebo within 3 hours of injury. The primary outcome was death from head injury within 28 days of injury. The methods and results are presented elsewhere. Fatigue was recorded as \u201cNone\u201d, \u201cModerate\u201d or \u201cExtreme.\u201d This study examines the effect of TXA on extreme fatigue in the 2,632 patients with mTBI (Glasgow Coma Scale [GCS] score\u226513). Our analyses were not prespecified. Results Our study primary outcome, extreme fatigue, was reported for 10 (0.8%) of 1,328 patients receiving TXA and 19 (1.5%) of 1,288 patients receiving placebo (risk ratio [RR]=0.51, 95% confidence interval [CI] 0.24-1.09). Death within 28 days of injury was reported for 34 (2.6%) of 1,328 patients receiving TXA versus 47 (3.6%) of 1,288 patients receiving placebo (RR=0.70, 95% CI 0.45-1.08). Among patients allocated to TXA, 44 (3.3%) patients either died or reported extreme fatigue versus 66 (5.1%) patients among those allocated to placebo (RR=0.65, 95% CI 0.44-0.94). This composite outcome is disproportionately influenced by deaths which account for 74% (81 from 110) of events. Conclusions We found no evidence that tranexamic acid reduces fatigue in patients with mTBI. Given, 1) our analyses were not prespecified, 2) our outcome measure is not based on a validated fatigue severity scale, and 3) TBI patients can suffer from hospital-induced delirium, which hinders clinician assessment, these results need to be replicated in another study. Registration ISRCTN (ISRCTN15088122, 19\/07\/2011), ClinicalTrials.gov (NCT01402882, 26\/07\/2011), EudraCT (2011-003669-14, 25\/07\/2011), Pan African Clinical Trial Registry (PACTR20121000441277, 30\/10\/2012).<\/ns3:p>","DOI":"10.12688\/wellcomeopenres.17421.3","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T05:55:10Z","timestamp":1730094910000},"page":"346","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Effect of early tranexamic acid treatment on fatigue in patients with mild traumatic brain injury: data from the CRASH-3 clinical trial"],"prefix":"10.12688","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9456-5859","authenticated-orcid":false,"given":"Raoul","family":"Mansukhani","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Belli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2017-5994","authenticated-orcid":false,"given":"Amy","family":"Brenner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5428-3988","authenticated-orcid":false,"given":"Rizwana","family":"Chaudhri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Frimley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabariah","family":"Faizah Jamaluddin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rashid","family":"Jooma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6511-109X","authenticated-orcid":false,"given":"Haleema","family":"Shakur-Still","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7819-6862","authenticated-orcid":false,"given":"Temitayo","family":"Shokunbi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1596-6054","authenticated-orcid":false,"given":"Ian","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2024,10,28]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"1080-1097","DOI":"10.3171\/2017.10.JNS17352","article-title":"Estimating the global incidence of Traumatic Brain Injury.","volume":"130","author":"M Dewan","year":"2019","journal-title":"J Neurosurg."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"56-87","DOI":"10.1016\/S1474-4422(18)30415-0","article-title":"Global, regional, and national burden of Traumatic Brain Injury and Spinal Cord Injury, 1990\u20132016: a systematic analysis for the Global Burden of Disease study 2016.","volume":"18","author":"S James","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref-3","doi-asserted-by":"publisher","first-page":"23-32","DOI":"10.1016\/S0140-6736(10)60835-5","article-title":"Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.","volume":"376","author":"H Shakur","year":"2010","journal-title":"Lancet."},{"key":"ref-4","doi-asserted-by":"publisher","first-page":"1713-1723","DOI":"10.1016\/S0140-6736(19)32233-0","article-title":"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.","volume":"394","year":"2019","journal-title":"Lancet."},{"key":"ref-5","first-page":"118-123","article-title":"Disability Rating scale for severe head trauma: coma to community.","volume":"63","author":"M Rappaport","year":"1982","journal-title":"Arch Phys Med Rehabil."},{"key":"ref-6","doi-asserted-by":"publisher","first-page":"1528-1538","DOI":"10.3109\/02699052.2010.531687","article-title":"Mild Traumatic Brain Injury and fatigue: a prospective longitudinal study.","volume":"24","author":"J Norrie","year":"2010","journal-title":"Brain Inj."},{"key":"ref-7","doi-asserted-by":"publisher","first-page":"416-425","DOI":"10.1017\/s1355617705050472","article-title":"Measurement and prediction of subjective fatigue following Traumatic Brain Injury.","volume":"11","author":"C Ziino","year":"2005","journal-title":"J Int Neuropsychol Soc."},{"key":"ref-8","doi-asserted-by":"publisher","first-page":"41-51","DOI":"10.1097\/01.HTR.0000308720.70288.af","article-title":"Fatigue after Traumatic Brain Injury and its impact on participation and quality of life.","volume":"23","author":"J Cantor","year":"2008","journal-title":"J Head Trauma Rehabil."},{"key":"ref-9","doi-asserted-by":"publisher","first-page":"563-576","DOI":"10.1080\/02699050010009108","article-title":"The prevalence and symptom rates of depression after Traumatic Brain Injury: a comprehensive examination.","volume":"15","author":"J Kreutzer","year":"2001","journal-title":"Brain Inj."},{"key":"ref-10","article-title":"Brain injury medicine: principles and practice","author":"N Zasler","year":"2007"},{"key":"ref-11","doi-asserted-by":"publisher","first-page":"841-848","DOI":"10.1080\/026990596123945","article-title":"Outcome following Traumatic Brain Injury: a comparison between 2 and 5 years after injury.","volume":"10","author":"J Olver","year":"1996","journal-title":"Brain Inj."},{"key":"ref-12","doi-asserted-by":"publisher","first-page":"2528-2541","DOI":"10.1089\/neu.2019.6898","article-title":"The prevalence and stability of Sleep-Wake Disturbance and fatigue throughout the first year after mild Traumatic Brain Injury.","volume":"37","author":"S Saksvik","year":"2020","journal-title":"J Neurotrauma."},{"key":"ref-13","article-title":"Effect of early tranexamic acid treatment on fatigue in patients with Mild Traumatic Brain Injury: data from the CRASH-3 clinical trial","author":"R Mansukhani","year":"2021"},{"key":"ref-14","article-title":"CRASH-3 trial protocol"},{"key":"ref-15","doi-asserted-by":"publisher","first-page":"86","DOI":"10.12688\/wellcomeopenres.14700.2","article-title":"Tranexamic acid for significant Traumatic Brain Injury (The CRASH-3 trial): statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial [version 2; peer review: 3 approved, 1 approved with reservations].","volume":"3","author":"I Roberts","year":"2018","journal-title":"Wellcome Open Res."},{"key":"ref-16","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2023-076316","article-title":"The estimands framework: a primer on the ICH E9(R1) addendum.","volume":"384","author":"B Kahan","year":"2024","journal-title":"BMJ."},{"key":"ref-17","doi-asserted-by":"publisher","first-page":"261-268","DOI":"10.1007\/s00068-020-01316-1","article-title":"Tranexamic acid in Traumatic Brain Injury: an explanatory study nested within the CRASH-3 trial.","volume":"47","year":"2021","journal-title":"Eur J Trauma Emerg Surg."},{"key":"ref-18","doi-asserted-by":"publisher","DOI":"10.1186\/s13063-020-04623-5","article-title":"Accuracy of time to treatment estimates in the CRASH-3 clinical trial: impact on the trial results.","volume":"21","author":"R Mansukhani","year":"2020","journal-title":"Trials."},{"key":"ref-19","doi-asserted-by":"publisher","first-page":"1121-3","DOI":"10.1001\/archneur.1989.00520460115022","article-title":"The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus.","volume":"46","author":"L Krupp","year":"1989","journal-title":"Arch Neurol."},{"key":"ref-20","doi-asserted-by":"publisher","first-page":"684-716","DOI":"10.1016\/j.neubiorev.2014.10.024","article-title":"A systematic review of fatigue in patients with Traumatic Brain Injury: the course, predictors and consequences.","volume":"47","author":"T Mollayeva","year":"2014","journal-title":"Neurosci Biobehav Rev."},{"key":"ref-21","doi-asserted-by":"publisher","first-page":"5-9","DOI":"10.1111\/j.1600-0404.1992.tb03987.x","article-title":"Minor Head Injury: impact on general health after 1 year. A prospective follow-up study.","volume":"85","author":"T Middelboe","year":"1992","journal-title":"Acta Neurol Scand."},{"key":"ref-22","doi-asserted-by":"publisher","first-page":"487-497","DOI":"10.1080\/026990596124205","article-title":"Prevalence of impairments 5 years after a Head Injury, and their relationship with disabilities and outcome.","volume":"10","author":"F Masson","year":"1996","journal-title":"Brain Inj."},{"key":"ref-23","doi-asserted-by":"publisher","first-page":"123-130","DOI":"10.1080\/14034940410028406","article-title":"Fatigue in the general population: a translation and test of the psychometric properties of the Norwegian version of the Fatigue Severity Scale.","volume":"33","author":"A Lerdal","year":"2005","journal-title":"Scand J Public Health."},{"key":"ref-24","doi-asserted-by":"publisher","first-page":"178-89","DOI":"10.1016\/j.nrleng.2024.01.008","article-title":"Fatigue in patients with acquired brain damage.","volume":"39","author":"A Ju\u00e1rez-Bela\u00fande","year":"2024","journal-title":"Neurologia (Engl Ed)."},{"key":"ref-25","doi-asserted-by":"publisher","DOI":"10.3390\/jcm13175154","article-title":"Symptom persistence relates to volume and asymmetry of the limbic system after mild Traumatic Brain Injury.","volume":"13","author":"C Vanier","year":"2024","journal-title":"J Clin Med."},{"key":"ref-26","doi-asserted-by":"publisher","first-page":"138-48","DOI":"10.1159\/000494988","article-title":"Inflammatory signaling in Post-Stroke Fatigue and depression.","volume":"80","author":"H Wen","year":"2018","journal-title":"Eur Neurol."},{"key":"ref-27","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD001886.pub2","article-title":"Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion.","author":"D Henry","year":"2007"},{"key":"ref-28","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-020-03243-4","article-title":"Understanding the neuroprotective effect of tranexamic acid: an exploratory analysis of the CRASH-3 randomised trial.","volume":"24","author":"A Brenner","year":"2020","journal-title":"Crit Care."}],"container-title":["Wellcome Open Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-346\/v3\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-346\/v3\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-346\/v3\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T05:50:16Z","timestamp":1731304216000},"score":1,"resource":{"primary":{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-346\/v3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,28]]},"references-count":28,"URL":"https:\/\/doi.org\/10.12688\/wellcomeopenres.17421.3","relation":{"has-version":[{"id-type":"doi","id":"10.12688\/wellcomeopenres.17421.2","asserted-by":"subject"},{"id-type":"doi","id":"10.12688\/wellcomeopenres.17421.1","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.21956\/wellcomeopenres.25699.r108636","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.25699.r108273","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.25699.r108636","asserted-by":"object"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.25699.r108273","asserted-by":"object"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.25699.r111410","asserted-by":"object"}]},"ISSN":["2398-502X"],"issn-type":[{"value":"2398-502X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,28]]},"assertion":[{"value":"Indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-346\/v3#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.19261.r76923, Kim Kirby, University of the West of England,, Bristol, 11 May 2024, version 1, 1 approved, 1 not approved","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-346\/v1#referee-response-76923","order":0,"name":"referee-response-76923","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.19261.r86356, Christie Fritz, Harvard Medical School, Boston, Massachusetts, 12 Aug 2024, version 1, 1 approved, 1 not approved","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-346\/v1#referee-response-86356","order":1,"name":"referee-response-86356","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Raoul Mansukhani<\/b>; \n<i>Posted: 27 Aug 2024<\/i>; Dear Dr Fritz,  Thank you for your comments which we have used to improve our article. When we were developing the CRASH-3 trial protocol we asked patient groups for their input. Their main suggestion was that we conduct an analysis of the impact of the trial treatment on fatigue because extreme fatigue is the symptom that patients find particularly troubling. We do not want to make any claim that is not supported by the data but we do feel an obligation to publish the results as promised. We accept that we may have overstated the potential of TXA to reduce this outcome.  Please see below for our responses: &nbsp; &nbsp;  \n<b>Comment 1:<\/b>&nbsp;Outcome measure: fatigue was assessed only by the clinician so isn\u2019t the patient centered outcome that we may necessarily hope for. Also, fatigue was measured either at hospital discharge (not as useful, since the hospital is a difficult place to measure fatigue at discharge), or at 28 days after injury while still inpatient. Hospital delirium would appear to be a significant factor in this, and I\u2019m concerned this is not as useful a marker\/outcome, especially as a patient centered marker. \n<b>Response:<i>&nbsp;<\/i><\/b>We\u2019ve changed the abstract conclusions to read: &nbsp; Given, 1) our analyses were not prespecified, 2) our outcome measure is not based on a validated fatigue severity scale, and 3) TBI patients can suffer from hospital-induced delirium, which hinders clinician assessment, these results need to be replicated in another study. We have added the following to the discussion: Our analysis was not prespecified, the precision of the estimates was low and our outcome measure is not based on a validated fatigue scale. In addition, TBI patients are prone to hospital-induced delirium which will hinder clinician assessment of fatigue. A larger trial is needed to test the hypothesis that early tranexamic acid treatment reduces fatigue in mTBI patients. ...... The CRASH-3 trial assessed fatigue via a three-point scale which hasn\u2019t been validated. We acknowledge this is a significant limitation with our study. Ideally, fatigue would be measured using a validated scoring system such as the 9 item Fatigue Severity Scale (FSS). We have removed the next sentence: However, studies that use more elaborate scoring systems with long questionnaires tend to have fewer participants and this would increase random error. Misclassification of an outcome variable usually biases towards the null. &nbsp;  \n<b>Comment 2:<\/b>&nbsp;They posit that severely injured patients are more likely to suffer effects from blood and would be less likely to benefit from TXA, but do not supply adequate references to make this assertion. \n<b>Response:<\/b> \n<i>I<\/i>n the discussion we have changed the sentence in the discussion: Although we planned to examine the impact of TXA treatment on extreme fatigue, the focus on mild TBI was not pre-specified but stimulated by the observation from the CRASH-3 intracranial bleeding mechanistic study\n<sup>17<\/sup>&nbsp;that patients with less severe TBI may have less intracranial bleeding at baseline and so there is more potential to prevent bleeding. &nbsp;  \n<b>Comment 3:<\/b>&nbsp;I have significant issues with the \u201ccomposite outcome\u201d of extreme fatigue or death. The authors didn\u2019t seem to get the results they were looking for with \u201cExtreme fatigue\u201d (only 1.1% of patients, most studies they say cite around 30%) in the GCS greater than or equal to 13 group so they added in death as an endpoint. There are more (34) patients with death as an outcome than extreme fatigue (10) in the treatment arm and I\u2019m concerned that it is the significance of death, not fatigue that are driving these outcomes, since either alone is not significant. These seem to be disparate outcomes that shouldn\u2019t be logically grouped together.&nbsp; \n<b>Response:<\/b> We have added the following to our methods: This composite outcome is consistent with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E9 guidelines\u2019 &quot;Composite strategy&quot; for handling intercurrent events. We have added the following sentence to the results section of the abstract: This composite outcome is disproportionately influenced by deaths which account for 74% (81 from 110) of events. We added the following sentence to the results section: This composite outcome is disproportionately influenced by deaths which account for 74 % (81 from 110) of events. We have also changed the conclusions of our study based on extreme fatigue alone rather the composite outcome of extreme fatigue and death. (See our response to comment 4 below) &nbsp;  \n<b>Comment 4:<\/b>&nbsp;I\u2019d also say that their discussion \u201csuggesting\u201d that TXA may reduce the risk of extreme fatigue is not borne out. Their CI crosses 1 and is not statistically significant in either of their analyses. I was also surprised that their first table, which they note were for patients with GCS of 13 or greater included those with no GCS recorded, which is not well explained. \n<b>Response:<\/b> We have changed the abstract conclusions to read: We found no evidence that tranexamic acid reduces fatigue in patients with mTBI. We changed the first sentence in our discussion to read: Our study found no evidence that tranexamic acid reduced fatigue in patients with mTBI. We replaced the sentence: The results of this study suggest that promptly treating mTBI patients with tranexamic acid may reduce risk of fatigue. With We were unable to demonstrate that tranexamic acid prevents fatigue in mTBI patients. &nbsp;  \n<b>Comment 5:<\/b>&nbsp;They also state \u201ccrash 3 trial showed that early treatment with TXA reduces head injury deaths in TBI patients, almost certainly by reducing intracranial bleeding\u201d which may be an overstatement of the conclusions of that paper.&nbsp; \n<b>Response:<\/b> We have changed our discussion to read: The CRASH-3 trial showed that early treatment with tranexamic acid reduces head injury deaths in mild and moderately injured TBI patients, potentially by reducing intracranial bleeding. &nbsp;  \n<b>Comment 6:<\/b>&nbsp;My biggest concern is their \u201ccomposite outcome\u201d of death or extreme fatigue. \n<b>Response:&nbsp;<\/b>We believe we have addressed this in points 3 and 4 above. I do hope you will &nbsp;be able to approve our article. &nbsp; Yours Sincerely &nbsp; Raoul Mansukhani Research fellow in medical statistics","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-346\/v3#referee-comment-5787","order":2,"name":"referee-comment-5787","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.25699.r108273, Vincenzo Menditto, Azienda Ospedaliero Universitaria delle Marche, Ancona, 04 Nov 2024, version 3, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-346\/v3#referee-response-108273","order":3,"name":"referee-response-108273","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.25699.r108636, Garima Yadav, All India Institute of Medical Sciences, Jodhpur, 05 Nov 2024, version 3, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-346\/v3#referee-response-108636","order":4,"name":"referee-response-108636","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Raoul Mansukhani<\/b>; \n<i>Posted: 09 Nov 2024<\/i>; Dear Dr Yadav,  Thank you for taking the time to review our article. The CRASH-3 trial steering committee included patient groups. These patient groups requested we conduct an analysis of the impact of the trial treatment on fatigue because extreme fatigue is the symptom that patients find particularly troubling. We therefore believe it is necessary to publish these results. Additionally, a criticism of medical research is the publication bias that arises from only publishing positive and statistically significant findings[1]. By publishing these results, we aim to avoid this pitfall.&nbsp; Regarding the biological plausibility: Saksvik[2] demonstrated an association between intercranial bleeding and fatigue in patients with mild traumatic brain injury (TBI). The CRASH-3 trial demonstrated that tranexamic acid given promptly reduces head injury deaths in patients with mild and moderate TBI[3], probably by reducing intracranial bleeding[4]. It therefore seems resonable to postulate that tranexamic acid might reduce fatigue in patients with mild TBI. Please let us know if you would like us to make any changes. Otherwise, we would appreciate your approval of our article.  Yours sincerely Raoul Mansukhani Research fellow in medical statistics  1. Hopewell S, Loudon K, Clarke MJ, Oxman AD, Dickersin K. Publication bias in clinical trials due to statistical significance or direction of trial results. Cochrane Methodology Review Group, editor. Cochrane Database of Systematic Reviews [Internet]. 2009 Jan 21 [cited 2024 Nov 8];2010(1).&nbsp;http:\/\/doi.wiley.com\/10.1002\/14651858.MR000006.pub3 2. Saksvik SB, Karaliute M, Kallestad H, Follestad T, Asarnow R, Vik A, et al. The Prevalence and Stability of Sleep-Wake Disturbance and Fatigue throughout the First Year after Mild Traumatic Brain Injury. Journal of Neurotrauma. 2020 Dec 1;37(23):2528\u201341.&nbsp; 3. CRASH-3 trial collaborators. 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. The Lancet. 2019 Nov;394(10210):1713\u201323.&nbsp; 4. The CRASH-3 Intracranial Bleeding Mechanistic Study Collaborators. Tranexamic acid in traumatic brain injury: an explanatory study nested within the CRASH-3 trial. Eur J Trauma Emerg Surg. 2021 Feb;47(1):261\u20138.&nbsp; &nbsp; &nbsp;","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-346\/v3#referee-comment-5902","order":5,"name":"referee-comment-5902","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The CRASH-3 trial was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (NIHR HTA; 14\/190\/01), the JP Moulton Charitable Trust, the Department of Health and Social Care, and the Wellcome Trust [105439] through a Joint Global Health Trials Scheme in low-middle income countries Grant funded by the UK Government Department for International Development, UK Medical Research Council and Wellcome Trust [MR\/M009211\/1]. The studies were designed, conducted, analysed, and interpreted by the investigators, entirely independently of all funding sources. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the funders. The funders had no role in the study design, the collection, analysis, or interpretation of the data, the writing of the report, or the decision to submit the paper for publication. The corresponding author had full access to all the data and had final responsibility for the decision to submit for publication. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":6,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}