The HALT-IT trial is an international, randomised, double blind, placebo-controlled trial to quantify the effects of TXA on morbidity and mortality in adults with significant upper or lower GI bleeding.
Blinding and randomisation
Pfizer Manufacturing, marketing authorisation number PL 00057 /0952, manufactures the tranexamic acid. Torbay and South Devon NHS Foundation Trust, manufacturing authorisation number MIA (IMP) 13079, manufactures the placebo (sodium chloride 0.9%). Sharp Clinical Services (UK) Ltd., manufacturing authorisation number MIA (IMP) 10284, manufactures the study drug treatment packs containing either the active drug tranexamic acid or placebo. The Marketing Authorisation guarantees that the product is manufactured and released in accordance with the UK’s Good Manufacturing Practice (GMP) regulations. Ampoules and packaging are identical in appearance.
An independent statistician from Sealed Envelope Ltd (UK) generates randomisation codes to be sent to Sharp Clinical Services UK Limited, a GMP certified clinical trial supplies company who prepare trial treatment packs in accordance with the randomisation list. Sharp Clinical Services conduct the blinding process and first stage Qualified Person (QP) release, which involves complete removal of the original manufacturer’s label and replacement with the clinical trial label bearing the randomisation number for use as the pack identification. Other pack label text are identical for tranexamic acid and placebo treatments and in compliance with requirements for investigational medicinal products. Sharp Clinical Services UK are also responsible for maintaining the Product Specification File (PSF) until final database lock and unblinding of the trial data. Quality control checks to assure the blinding process are performed on a random samples of final QP released drug packs. High Performance Liquid Chromatography (HPLC) separation of known TXA is assessed against blinded samples to confirm which ampoule contains the placebo and active treatment. The tested samples are unblinded to assure accuracy of blinding.
The Trial Coordinating Centre (TCC) is responsible for assuring all relevant approvals are available at the TCC before release of the trial treatment to a site. A separate Manual of Operating Procedures details the drug accountability system. The Investigator’s Brochure details labelling of the trial treatment and other processes for assuring adherence to Good Manufacturing Practice.
Eligible patients are randomised to receive either tranexamic acid or placebo as soon as possible and the study treatment started immediately. The next consecutively numbered treatment pack is taken from a box of eight packs. A fixed loading dosage of 1 g tranexamic acid or placebo (sodium chloride 0.9%) is administered, followed by a maintenance dose of 3 g tranexamic acid of placebo (sodium chloride 0.9%) infused over 24 hours.
Ethics approval and consent
The trial was approved by the UK NRES Committee East of England (reference number 12/EE/0038), as well as national and local research ethics committees of participating countries outside of the UK.
Acute severe GI bleeding can be a frightening condition for the patient and the ensuing blood loss may have adverse impact on the patient’s mental and emotional state, impairing their decision-making ability. The consent procedures consider this together with the need to randomise and treat urgently. If the patient is fully competent, written consent is sought. If the patient’s capacity is impaired and a personal or professional representative is available, consent is sought from the representative. If neither are able to provide informed consent, consent is waived and the patient is informed about the trial as soon as it is possible.
The entry form (Appendix 1) is used to assess eligibility and collect baseline information. Once a patient has been randomised, the outcome in hospital is collected even if the trial treatment is interrupted or is not actually given. No extra tests are required but a short outcome form (Appendix 2) is completed from the medical records 28 days after randomisation or on discharge from the randomising hospital or on death (whichever occurs first). Any adverse events that become known to the investigator are reported up to 28 days after randomisation.
We originally specified all-cause mortality as the primary outcome because we believed that most deaths would be due to bleeding. However, as the trial was underway we observed that over half of all deaths were due to non-bleeding causes such as cancer and sepsis (see Figure 1). Tranexamic acid reduces bleeding by inhibiting fibrinolysis. Based on this mechanism of action, we do not expect any substantial reduction in non-bleeding deaths. This hypothesis is supported by evidence from trials of tranexamic acid in trauma and postpartum haemorrhage [39,40,43]. As such, the treatment effect on all-cause mortality will be diluted by non-bleeding causes of death, reducing statistical power .
Death due to bleeding is the relevant endpoint for the HALT-IT trial because it has the potential to be reduced by the trial treatment. Fibrinolysis may play an important role in GI bleeding: gastric vein blood samples from patients with peptic ulcers contain high concentrations of plasmin and many patients with acute upper GI bleeding have elevated levels of fibrin degradation products (a biomarker for fibrinolysis) which is associated with worse outcomes [44–46]. The rationale for changing the primary outcome from all-cause mortality to death due to bleeding was published in October 2018 . The decision was supported by the Trial Steering Committee and was made prior to the end of the trial and prior to un-blinding and so was not a data-dependent change.
Assuming a cumulative incidence of death due to bleeding of 4%, a study with 12,000 patients will have 85% power (two sided alpha = 5%) to detect a clinically important 25% relative reduction in death due to bleeding from 4% to 3%.
Patients with significant GI bleeding to whom the uncertainty principle applies are eligible. Specifically, a patient can be enrolled if the responsible clinician is substantially uncertain as to whether the trial treatment is appropriate for that particular patient. Significant bleeding is diagnosed clinically and implies a risk of bleeding to death. Patients with significant bleeding may include those with hypotension, tachycardia, signs of shock, or those needing urgent transfusion, endoscopy or surgery. Patients with a clear indication or contraindication for tranexamic acid are excluded.
Recruitment, withdrawal and loss to follow-up
We will display the flow of study participants using a Consolidated Standards of Reporting Trials (CONSORT) diagram (see Appendix Figure 1). For each trial arm, we will present the total number randomised, the number with baseline data, the number lost to follow up, the number who withdrew consent, and the number of participants with outcome data.
Baseline patient characteristics
We collect data on the following baseline characteristics: age, sex, time from onset of GI bleeding symptoms to randomisation, suspected location of bleeding, clinical symptoms (e.g. haematemesis, melaena), suspected variceal bleeding, systolic blood pressure, heart rate, signs of shock, suspected active bleeding, major comorbidities, anticoagulation therapy and type of admission. We will present the distribution of baseline characteristics (n and %) in the treatment and placebo groups to check that randomisation was successful in producing similar groups (see Appendix Table 1).
The main analysis will compare death due to bleeding in those allocated tranexamic acid with those allocated placebo on an intention-to-treat basis. We will present the results as effect estimates (relative risks) with a measure of precision (95% confidence intervals) and p-value from Pearson’s chi-squared test (see Appendix Table 2). The effect of tranexamic acid will also be examined graphically using cumulative incidence curves (see Appendix Figure 2) . The effects of TXA on death due to bleeding in the HALT-IT trial will be set in the context of other trials of TXA in acute severe haemorrhage (The CRASH-2 and Woman trials).
Death due to bleeding within five days of randomisation is the primary outcome. Patients receive tranexamic acid (or placebo) for their initial bleed but not for rebleeding episodes. Tranexamic acid has a half-life of 2-3 hours so 99% will be eliminated within about 2 days of randomisation [48,49]. We do not expect tranexamic acid to reduce deaths from a rebleeding episode several weeks after the drug has been fully eliminated, therefore the primary outcome will consider early deaths due to bleeding only. Cause of death is assigned by local investigators who provide a narrative of the events leading to death. The cause of death narratives are reviewed by the principal investigator (who is blind to treatment allocation) and queried if more information is needed to confirm whether death is due to bleeding or another cause.
Rebleeding occurs in approximately 10-25% of patients with acute GI haemorrhage and is associated with an increased risk of death due to bleeding . A clinical diagnosis of rebleeding is made by the treating clinician based on the presence of any of the following criteria, as defined in a data collection guide. These criteria for rebleeding were recommended by a methodological framework for trials in GI bleeding following an international consensus conference .
Haematemesis or bloody NG aspirate > 6 hours after endoscopy.
Melaena after normalisation of stool colour.
Haematochezia after normalisation of stool colour or after melaena.
Development of tachycardia (HR>110 beats per min) or hypotension (SBP<=90mmHg) after ≥1 hour of haemodynamic stability (i.e. no tachycardia or hypotension) in the absence of an alternative explanation for haemodynamic instability, such as sepsis, cardiogenic shock, or medication
Haemoglobin drop of >2g/dl after two consecutive stable values(<0.5g/dl decrease) ≥3hours apart
Tachycardia or hypotension that does not resolve within 8 hours after index endoscopy despite appropriate resuscitation (in the absence of an alternative explanation) associated with persistent melaena or haematochezia.
Persistently dropping haemoglobin of >3g/dl in 24 hours associated with persistent melaena or haematochezia
It should be noted that patients may continue to have haemodynamic instability, falling haemoglobin levels or persistent melaena or rectal bleeding for hours and even days after bleeding has stopped, making these patients difficult to categorise; however, these criteria are more likely to indicate rebleeding than equilibration .
Rebleeding within 5 days
Most rebleeding tends to occur within 5 days of the index bleed [35–37]. We believe tranexamic acid will be most effective at reducing the risk of rebleeding soon after the index bleed when blood plasma concentrations of the drug are above the level needed to inhibit fibrinolysis . To determine whether tranexamic acid reduces rebleeding, we will analyse the effect on early rebleeding within 5 days of randomisation (see Appendix Table 2).
Rebleeding within 28 days
Rebleeding that occurs more than 5 days after randomisation will be defined as late rebleeding. We hypothesise that tranexamic acid will be much less effective for late rebleeding occurring days or weeks after the drug has been eliminated. To investigate this we will assess the effect of tranexamic acid on rebleeding within 28 days (see Appendix Table 2). If our hypothesis is correct, the inclusion of late rebleeding events will dilute the treatment effect.
Death due to bleeding within 28 days
As with late rebleeding, we do not expect tranexamic acid to have an effect on late deaths due to bleeding that occur several days after randomisation. To assess this we will analyse the effect of tranexamic acid on death due to bleeding within 28 days of randomisation (see Appendix Table 2). We expect to observe a smaller treatment effect when including late deaths due to bleeding.
We will analyse the effect of tranexamic acid on all-cause and cause-specific mortality at 28 days. Specific causes of death to be analysed include death due to bleeding, thrombosis, organ failure, pneumonia, sepsis, malignancy and other causes (see Appendix Table 3). We will also examine the temporal distribution of causes of death by days since randomisation using a frequency bar chart (see Appendix Figure 3). Based on its mechanism of action and data from large randomised trials, we do not expect tranexamic acid to reduce deaths from non-bleeding causes like cancer or sepsis or to reduce late deaths from bleeding.
Endoscopic, radiological and surgical procedures for GI bleeding
It remains unclear whether tranexamic acid reduces the need for surgery in GI bleeding . In large trials of tranexamic acid for postpartum and traumatic haemorrhage, there was no effect on surgical interventions except for laparotomy for bleeding [39,40]. If tranexamic acid reduces GI bleeding, it has the potential to reduce the need for some surgical, endoscopic and radiological procedures. While we do not expect tranexamic acid to influence diagnostic endoscopic and radiological procedures planned around the time of hospital admission and randomisation, there is potential to reduce the need for diagnostic procedures planned after resuscitation, and therefore after randomisation . Similarly, therapeutic procedures and surgical interventions planned and undertaken after diagnosis also have the potential to be influenced by tranexamic acid. We will assess the effect of tranexamic acid on diagnostic and therapeutic endoscopic and radiological procedures and surgical interventions (see Appendix Table 5). It is not possible to look at procedures by time as this information was not recorded.
Since blood transfusion is mostly determined by blood loss prior to randomisation, we do not expect to see a marked reduction in the need for blood transfusion with use of tranexamic acid . Major haemorrhage protocols dictate the type and volume of blood components patients receive based on presenting clinical signs such as blood pressure and estimated blood loss. Furthermore, survivor bias could lead to higher transfusion rates in the tranexamic acid group. In keeping with this, a systematic review of tranexamic acid for GI bleeding found no reduction in transfusion . Although tranexamic acid has the potential to reduce transfusion for blood lost after randomisation e.g. after rebleeding, we did not collect data on date and time of transfusion. Any effect on late transfusions is likely to be obscured by early transfusions for blood lost pre-randomisation. We will assess the effect of tranexamic acid on the use of whole blood or packed red cells, frozen plasma and platelets comparing the frequency of transfusion and the mean number of (adult-equivalent) units transfused (see Appendix Table 5).
An individual patient data meta-analysis of the WOMAN and CRASH-2 trials found no increased risk of vascular occlusive events with tranexamic acid . While this finding is reassuring, we cannot exclude the possibility of some increased risk with TXA, particularly as patients with GI bleeding are older than those with traumatic or postpartum haemorrhage and many have multiple co-morbidities. Older age is associated with a pro-coagulation haemostatic profile including elevated fibrinogen and plasminogen activator inhibitor 1 and reduced clotting time [54–56]. A systematic review of tranexamic acid for the treatment of upper GI bleeding found no difference in the risk of thromboembolic events but lacked power . We will examine the effect of tranexamic acid on fatal and non-fatal pulmonary embolism, deep vein thrombosis, stroke and myocardial infarction (see Appendix Table 6).
We will analyse the effect of tranexamic acid on renal, hepatic and respiratory failure, cardiac events, sepsis, pneumonia and seizures (see Appendix Table 6). If tranexamic acid reduces death due to bleeding, patients in the tranexamic group will survive for longer on average and may therefore be at greater risk of complications such as sepsis, pneumonia and organ failure. Generally, death due to bleeding tends to occur soon after bleeding onset whereas infections and organ failure take several days to occur. On the other hand, if tranexamic acid reduces bleeding it may reduce liver failure because bleeding can lead to the deterioration of liver function. Although there is evidence that high-dose tranexamic acid can cause seizures, we do not expect to see an increase in seizures with the low dose given in the trial.
Patients self-care capacity will be measured using the Katz Index of Independence in Activities of Daily Living (Katz ADL) . Participants’ performance in six functions (bathing, dressing, toileting, transferring, continence and feeding) is assessed at the time of discharge from the randomising hospital or in-hospital 28 days after randomisation. A score of 1 is assigned to each function the individual can perform independently and they are summed to produce a total score. A score of 6 suggests full function, 4 suggests moderate impairment, and 2 or less suggests severe functional impairment. We expect that reduced blood loss in patients who receive tranexamic acid will result in less functional impairment. To assess this hypothesis we will compare the difference in mean Katz ADL score in the tranexamic acid and placebo groups as well as the proportion of patients with no impairment (6), mild to moderate impairment (3-5) or severe impairment (0-2), (see Appendix Table 6).
Days spent in intensive care or high dependency unit
We will analyse the effect of tranexamic acid on number of days spent in the intensive care unit (ICU) or high dependency unit (HDU). We will compare the difference in mean number of days spend in the ICU or HDU in the tranexamic acid and placebo groups (see Appendix Table 6). Because beds in these units can be limited, we may not see an effect on this outcome measure.
Data on the number of adverse events (AEs), serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs) reported up to 28 days after randomisation will be presented. We will present a summary table in an appendix to describe the type of AE, Medical Dictionary for Regulatory Activities (MedDRA) preferred term (PT), MedDRA system organ class (SOC) and the number of occurrences and outcomes (completely recovered, recovered with sequelae, or died) in the tranexamic acid and placebo groups. With events grouped by MedDRA SOC, we will compare the frequency of events between trial arms using a chi-squared test or Fisher’s exact test (see Appendix Table 7). AEs with evidence that they may be increased by tranexamic acid (i.e. seizures and thromboembolic events), will be analysed on an individual basis as well as recurrent episodes of gastrointestinal bleeding reported as Aes.
We will conduct the following subgroup analyses for the primary outcome of death due to bleeding: time to treatment, location of bleeding, cause of bleeding and clinical Rockall score. We will fit interaction terms with randomised group in a Poisson regression model with robust error variance. Interaction tests (the Wald test) will be used to explore whether the effect of treatment (if any) differs across these subgroups. Results will be presented as crude and adjusted effect estimates with a measure of precision (95% confidence intervals) and p-value (see Appendix Table 4). Significant heterogeneity between subgroups is required and not just significance of a result in a specific subgroup . Selection of potential confounders is based upon review of unblinded data within the trial to date.
Several baseline characteristics are associated with the subgroup variables. We will adjust for potential confounders including age, time to treatment, systolic blood pressure, heart rate, signs of shock, location of bleeding, suspected active bleeding, comorbid liver disease and suspected variceal bleeding. For example, early treatment is correlated with certain bleed characteristics and patient characteristics (see Figure 2). Some of these characteristics confer a higher clinical Rockall score suggesting patients with more severe bleeding are treated earlier. Since these factors are also associated with mortality, they could confound the interaction between time to treatment and the treatment effect. Signs of shock may be collinear with heart rate or blood pressure, and suspected variceal bleeding may be collinear with comorbid liver disease – if so, signs of shock and suspected variceal bleeding will not be included in the models.
Time to treatment (<=3h, >3h)
Trials of tranexamic acid in traumatic and postpartum haemorrhage provide evidence that early treatment (within 3 hours of bleeding onset) confers the most benefit, while late treatment is ineffective [39,53,59]. As such, we plan to conduct a subgroup analysis of the treatment effect stratified by time to treatment. Patients with GI bleeding may not experience symptoms immediately so time of symptom onset accurately reflect time of bleeding onset. Time to treatment may therefore be underestimated. Because few patients are treated early (within 3 hours), there may be low power to detect an interaction if one exists. As such, we will analyse time to treatment as both a categorical (<=3h, >3h) and continuous variable because the latter will preserve more information so should have more power.
Because there is prior evidence to expect a time to treatment interaction, we do not require as strong evidence against the null hypothesis of homogeneity as we might usually require. Most trials lack power to detect heterogeneity in treatment effects and the lack of a statistically significant interaction does not mean that the overall treatment effect applies to all patients. Due to prior evidence that early treatment is more effective, we will consider the time to treatment subgroup analysis in the context of the existing data (in particular data from the CRASH-2 and WOMAN trials) on the time to treatment interaction and will rely more on scientific judgment than on statistical tests.
Location of bleeding (upper GI, lower GI)
We will examine the effect of tranexamic acid on death due to bleeding stratified by location (upper versus lower GI). Evidence suggests the rates of rebleeding and mortality after upper and lower GI bleeding are similar , and there is no reason to expect the effect of tranexamic acid to vary substantially by location of bleeding in the GI tract. Unless there is strong evidence against the null hypothesis of homogeneity of effects (i.e. p<0.001), the overall relative risk will be considered the most reliable guide to the approximate treatment effect in all patients.
Suspected variceal bleeding and comorbid liver disease (yes, no/unknown)
Outcomes in acute GI bleeding vary by cause of haemorrhage. Variceal bleeding is associated with the highest risk of rebleeding and death. Oesophageal varices are dilated submucosal veins that usually develop because of portal hypertension, often due to cirrhosis. Haemostasis is disturbed in patients with liver disease because many of the pro- and anti-coagulation factors and components of the fibrinolytic system are produced by hepatic parenchymal cells in the liver, although the overall sum of effects are debated [60–62]. Any resulting imbalance in coagulation or fibrinolysis may alter the antifibrinolytic activity of tranexamic acid; however, the direction of this potential effect remains to be determined. We will examine the effects of tranexamic acid on death due to bleeding in patients with suspected variceal bleeding and comorbid liver disease compared to other or unknown causes of bleeding. Unless there is strong evidence against the null hypothesis of homogeneity of effects (i.e. p<0.001), the overall relative risk will be considered the most appropriate measure of effect.
Clinical Rockall score (1-2, 3-4, 5-7)
We will assess the effect of tranexamic acid stratified by the clinical (pre-endoscopy) Rockall score, a widely used risk scoring system for GI bleeding. The score is derived from age, comorbidities, signs of shock, heart rate and systolic blood pressure, all of which are independent predictors of mortality. Although originally developed for upper GI bleeding , the Rockall score has also been shown to be predictive of mortality in lower GI bleeding . We do not expect the treatment effect to vary by Rockall score. Unless there is strong evidence of an interaction (p<0.001), we will present to overall relative risk as the most appropriate measure of effect.
Per protocol analysis
We will conduct a per protocol analysis of the effect of tranexamic acid on death due to bleeding and thromboembolic events excluding patients who received neither the loading nor maintenance dose or received off-label TXA during the trial. We expect to observe a slightly larger treatment effect in the per-protocol analysis. If some patients allocated tranexamic acid did not actually receive it then the treatment group will be more similar to the placebo group, thereby diluting the treatment effect. Similarly, if some patients in the placebo group receive off-label TXA, this will also dilute the treatment effect.
Based on the data collected to date, we expect loss to follow-up to be minimal (i.e. less than 1% missing data on the primary outcome). Any missing values will be reported but not imputed.
Other analyses to be reported in separate publications
Survival analysis to investigate the timing and duration of the treatment effect
We will conduct a survival analysis to explore the effect of tranexamic acid on rebleeding and death due to bleeding in more detail. In large trials of tranexamic acid for traumatic (CRASH-2) and postpartum haemorrhage (WOMAN), there were few late bleeding-related events. The precise timing and duration of tranexamic acid’s antifibrinolytic effect remain to be determined. For example, it is unclear whether the treatment effect persists after the drug has been eliminated. Bleeding-related events occur later in acute GI bleeding, partly due to rebleeding, so the HALT-IT trial presents a unique opportunity to investigate this question.
We will report the median survival time and the cumulative incidence in the treatment and placebo groups, and model the treatment effect. Cox proportional hazards modelling assumes the hazards in the treatment and placebo groups are proportional over time. This assumption may be invalid if the antifibrinolytic effect of tranexamic acid declines over time as the drug is metabolised. We will formally assess this using the Royston-Palmer test for proportional hazards - a combined test with increased power when an early treatment effect is present . If the treatment effect on death due to bleeding and rebleeding appears to change with time (non-proportional hazards), we will examine this in detail using various methods, firstly by including a time by treatment interaction term in the model. We will also estimate average cumulative hazard ratios for increasingly longer periods of follow-up. This method is preferred to period-specific hazard ratios, which can be susceptible to selection bias . Nevertheless, we will also use lexis expansion to calculate period-specific hazard ratios and test for interactions between treatment group and period. If we are able to identify the average duration of the treatment effect, we will examine whether this varies by baseline characteristics including time to treatment, bleeding severity, cause of bleeding and age.
Death due to bleeding is a competing risk for non-bleeding causes of death and vice versa. Death is also a competing risk for rebleeding. We will estimate the treatment effect using a proportional cause-specific hazards model in which competing events are censored. The proportional cause-specific hazards model is preferred for aetiological research; however, both the cause-specific hazard and cumulative incidence can provide insights into a treatment’s effects [65,66]. As such, a subdistribution hazards model and Gray’s test for comparing cumulative incidence functions will be presented as a supplementary analysis [67,68]. Risk of rebleeding is highest immediately after the index bleed, death is a competing risk for rebleeding and some patients may experience more than one episode during the follow-up period. A survival analysis of the effect of tranexamic acid on rebleeding will take into account timing of events, competing risks and dependence among repeated events.
Cost effectiveness analysis
If the trial demonstrates that tranexamic acid is an effective treatment for GI bleeding, we will conduct an economic evaluation to determine cost-effectiveness. Broadly speaking the methods will mirror those used by Li et al. who assessed the cost-effectiveness of tranexamic acid for the treatment of women with post-partum haemorrhage .
The analysis will compare tranexamic acid against clinical practice without tranexamic acid. A cost-utility analysis will be performed from a health services cost perspective with outcomes expressed as Quality-Adjusted Life-Years (QALYs). The analyses will be performed separately for a set of different countries, depending on where the majority of people have been recruited, but is likely to include at least the UK and Pakistan. A decision model will be used to extrapolate results from the trial into the longer term. Resource data, such as drugs and length of inpatient stay, are collected as part of the trial and will be analysed accordingly. Both deterministic and probabilistic sensitivity analysis will be undertaken. Results will also be presented by subgroups if considered appropriate.
Impact of baseline risk on treatment effectiveness
To assess whether the effect of tranexamic acid on death due to bleeding varies by baseline risk we will build a prognostic model using baseline characteristics identified as important predictors of death due to bleeding. Prognostic factors include age, systolic blood pressure, heart rate, suspected location of bleeding, haemetamesis/coffee ground vomitus, suspected variceal bleeding, suspected active bleeding, comorbidities and country. The prognostic model will then be used to stratify patients by risk of mortality and stratum-specific effect estimates (relative risk) and 95% confidence intervals will be calculated. We do not expect the treatment effect to vary by baseline risk. Unless there is strong evidence against the null hypothesis of homogeneity of effects (P<0.001), the overall relative risk will be considered the most reliable guide to the approximate treatment effect in all patients.
Adjustment for baseline risk
Due to the large size of the HALT-IT trial, baseline characteristics should be well balanced between the treatment and placebo groups so that any differences in outcomes is due to the treatment. There is still a small possibility, however, that some imbalance in baseline risk may have arisen by chance. If prognostic factors are distributed differently across the treatment and placebo groups, this could bias the treatment effect. To investigate this hypothesis, we will conduct an analysis of the treatment effect on death due to bleeding adjusted for baseline risk. Patients will be stratified by risk deciles based on the predicted probability of death due to bleeding and a pooled effect estimate (relative risk) will be calculated using inverse variance weighting. This will provide an estimate of the treatment effect un-confounded by baseline risk.
Centre and country effects
Centre and country-level characteristics can influence patient outcomes. Differences in outcome may be related to resource availability or clinical practice. To explore between-country differences we will present a graph showing the number of patients and bleeding deaths by country and will use multivariable regression modelling to examine the treatment effect by country, including an interaction term between county and treatment. We will adjust for potential confounders including age, systolic blood pressure, heart rate, comorbidities, location of bleeding, suspected variceal bleeding, suspected active bleeding and time to treatment. A comparison between low, middle and high-income countries will be included using the World Bank country groupings by income. We do not expect the effect of tranexamic acid on the risk of death due to bleeding to vary by country, even though the absolute risk will vary due to between-country differences in patient populations. Countries recruiting less than 100 patients will be omitted from the analysis as necessary.
Between-centre differences in outcome may also influence the estimation of the treatment effect. We will first use a random effects regression model to examine whether there are differences in death due to bleeding between centres. Results will be presented in the form of a forest plot. Prognostic patient characteristics (age, systolic blood pressure, heart rate, comorbidities, location of bleeding, suspected variceal bleeding, suspected active bleeding), treatment group and time to treatment will be adjusted for. To take into account country-level effects we will also consider between-centre differences in outcome adjusted for country. We will then use fixed and random effects regression to estimate the treatment effect before and after accounting for between-centre differences, assuming a constant treatment effect across centres. To assess whether the treatment effect differs by centre, will fit a model with an interaction term between centre and treatment.
The progress of the HALT-IT trial, including recruitment, data quality, outcomes and safety data, are reviewed by an independent Data Monitoring Committee, which can decide to reveal unblinded results to the Trial Steering Committee. To date, four interim analyses have been conducted.
To maximise data utilisation and improve patient care, the trial data will be made available via our online data-sharing portal - The Free Bank of Injury and emergency Research Data (freeBIRD) (http://freebird.Lshtm.ac.uk) - once primary and secondary analyses have been published.
The study has been actively recruiting since July 2013. End of recruitment is planned for 31 May 2019, with end of follow-up expected on 30 June 2019. Further information is available at http://haltit.Lshtm.ac.uk/.