Trial management: we need a cadre of high-class triallists to deliver the answers that patients need.

Expert trial managers with the training and experience to overcome operational challenges are often the difference between the success and failure of a clinical trial. Considerable importance is given to the beginning and the end of the clinical trial process, with those responsible for writing a protocol, obtaining funding and analysing the data all being rewarded when the results are published. Yet, trial managers are often overlooked in terms of recognition, value and status. This article highlights some of the key barriers to achieving this and makes suggestions on how they can be addressed within clinical trials units registered with the UK Clinical Research Collaboration

Effect of tranexamic acid on coagulation and fibrinolysis in women with postpartum haemorrhage (WOMAN-ETAC): a single-centre, randomised, double-blind, placebo-controlled trial

Background: Postpartum haemorrhage (PPH) is a leading cause of maternal death. The WOMAN trial showed that tranexamic acid (TXA) reduces death due to bleeding in women with PPH. We evaluated the effect of TXA on fibrinolysis and coagulation in a sample of WOMAN trial participants. Methods: : Adult women with a clinical diagnosis of PPH were randomised to receive 1 g TXA or matching placebo in the WOMAN trial. Participants in the WOMAN trial at University College Hospital (Ibadan, Nigeria) also had venous blood taken just before administration of the first dose of trial treatment and again 30 (±15) min after the first dose (the ETAC study).  We aimed to determine the effects of TXA on fibrinolysis (D-dimer and rotational thromboelastometry maximum clot lysis (ML)) and coagulation (international normalized ratio and clot amplitude at 5 min). We compared outcomes in women receiving TXA and placebo using linear regression, adjusting for baseline measurements. Results: : Women (n=167) were randomised to receive TXA (n=83) or matching placebo (n=84). Due to missing data, seven women were excluded from analysis. The mean (SD) D-dimer concentration was 7.1 (7.0) mg/l in TXA-treated women and 9.6 (8.6) mg/l in placebo-treated women (p=0.09). After adjusting for baseline, the D-dimer concentration was 2.16 mg/l lower in TXA-treated women (-2.16, 95% CI -4.31 to 0.00, p=0.05). There was no significant difference in ML between TXA- and placebo-treated women (12.3% (18.4) and 10.7% (12.6), respectively; p=0.52) and no significant difference after adjusting for baseline ML (1.02, 95% CI -3.72 to 5.77, p=0.67).  There were no significant effects of TXA on any other parameters. Conclusion: TXA treatment was associated with reduced D-dimer levels but had no apparent effects on thromboelastometry parameters or coagulation tests. Registration: ISRCTN76912190 (initially registered 10/12/2008, WOMAN-ETAC included on 22/03/2012) and NCT00872469 (initially registered 31/03/2009, WOMAN-ETAC included on 22/03/2012)

The WOMAN Trial: Clinical and Contextual Factors Surrounding the Deaths of 483 Women Following Post-Partum Hemorrhage in Developing Countries

The etiology of maternal mortality is postpartum hemorrhage in approximately 8.0% of cases in developed countries and 19.7% in developing countries. As a leading cause of maternal death, its prevention and early treatment are a priority. As part of the WOMANTrial, a randomized trial of tranexamic acid to treat postpartum hemorrhage, information on the causes ofmaternal death was recorded. The aim of this study was to review the circumstances of maternal death inmore than 20,000 women in 21 countries. The WOMAN Trial demonstrated that tranexamic acid reduced maternal death in women with postpartum hemorrhage. The study took place between 2010 and 2016 in 193 hospitals in 21 countries and recruited 20,060 women who were 16 years or older and were diagnosed with postpartumhemorrhage following vaginal or cesarean deliveries. In cases ofmaternal death, obstetricians were asked to record the cause of death and provide a brief narrative of the circumstances surrounding the death. Of the 20,060 women recruited for the trial, 12,343 were from Africa, 6030 from Asia, and 1049 from Europe. A total of 483 deathswere recorded, with case fatality rates of 3.0%(n = 375) in Africa and 1.7%(n = 105) in Asia; there were no deaths in the European cohort. Narratives were obtained for 52% of the recorded deaths. The odds of maternal death were 5 times higher in cases involving stillbirths versus live births (odds ratio = 5.26, 95%confidence interval = 4.34 6.39). The risk of death was also associated with more than 1000 mL of blood loss, a systolic blood pressure of <90 mm Hg, and hemodynamic instability. Among the 483 deaths, 13.3% were women who died within 3 hours of delivery and 59.8% who died between 3 and 24 hours after delivery. Women who gave birth outside of a participating hospital were 3 times more likely to die than those who gave birth at a participating hospital (odds ratio = 3.12, 95% confidence interval = 2.55 3.81). Based on the narratives, women who gave birth elsewhere were often in critical condition upon their arrival at a participating hospital. Bleeding was the most common cause of death for 346 women (72%). Bleeding was the cause of death for 91% of women who died within 3 hours of delivery and 83% of those who died within 24 hours of delivery. The primary cause of bleeding was uterine atony (53.2%). On average, women who died lost 2.1 L of blood (SD = 0.9 L, median = 2 L, interquartile range = 1.5 2.5 L) versus 1.2 L of blood for women who lived (SD = 0.6 L, median = 1 L, interquartile range = 0.8 1.5 L). More women who died received blood transfusions than those who lived (92.1% vs 53.8%). The narratives noted that blood was often unavailable for transfusion because of blood shortages or the family's inability to purchase blood. In this study, blood loss was observed to be the leading cause of death in women fromAfrica and Asia. Achieving mortality rates in developing countries similar to those in developed countries will require attention to issues such as late presentation due to births outside of hospitals and the lack of blood for transfusion

Postpartum haemorrhage in anaemic women: assessing outcome measures for clinical trials.

BACKGROUND: Postpartum haemorrhage (PPH) is a leading cause of maternal mortality worldwide. Maternal anaemia greatly increases the risk of PPH, and over a third of all pregnant women are anaemic. Because anaemia reduces the oxygen-carrying capacity of the blood, anaemic women cannot tolerate the same volume of blood loss as healthy women. Yet the same blood loss threshold is used to define PPH in all women. The lack of an established PPH definition in anaemic women means the most appropriate outcome measures for use in clinical trials are open to question. We used data from the WOMAN-2 trial to examine different definitions of PPH in anaemic women and consider their appropriateness as clinical trial outcome measures. MAIN BODY: The WOMAN-2 trial is assessing tranexamic acid (TXA) for PPH prevention in women with moderate or severe anaemia at baseline. To obtain an accurate, precise estimate of the treatment effect, outcome measures should be highly specific and reasonably sensitive. Some outcome misclassification is inevitable. Low sensitivity reduces precision, but low specificity biases the effect estimate towards the null. Outcomes should also be related to how patients feel, function, or survive. The primary outcome in the WOMAN-2 trial, a 'clinical diagnosis of PPH', is defined as estimated blood loss > 500 ml or any blood loss within 24 h sufficient to compromise haemodynamic stability. To explore the utility of several PPH outcome measures, we analysed blinded data from 4521 participants. For each outcome, we assessed its: (1) frequency, (2) specificity for significant bleeding defined as shock index ≥1.0 and (3) association with fatigue (modified fatigue symptom inventory [MFSI]), physical endurance (six-minute walk test) and breathlessness. A clinical diagnosis of PPH was sufficiently frequent (7%), highly specific for clinical signs of early shock (95% specificity for shock index ≥1) and associated with worse maternal functioning after childbirth. CONCLUSION: Outcome measures in clinical trials of interventions for PPH prevention should facilitate valid and precise estimation of the treatment effect and be important to women. A clinical diagnosis of PPH appears to meet these criteria, making it an appropriate primary outcome for the WOMAN-2 trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT03475342, registered on 23 March 2018; ISRCTN62396133, registered on 7 December 2017; Pan African Clinical Trial Registry PACTR201909735842379, registered on 18 September 2019

Tranexamic acid for the prevention of postpartum bleeding in women with anaemia: study protocol for an international, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Postpartum haemorrhage (PPH) is responsible for about 100,000 maternal deaths every year, most of which occur in low- and middle-income countries. Tranexamic acid (TXA) reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots. TXA decreases blood loss in surgery and reduces death due to bleeding after trauma. When given within 3 h of birth, TXA reduces deaths due to bleeding in women with PPH. However, for many women, treatment of PPH is too late to prevent death. Over one third of pregnant women in the world are anaemic and many are severely anaemic. These women have an increased risk of PPH and suffer more severe outcomes if PPH occurs. There is an urgent need to identify a safe and effective way to reduce postpartum bleeding in anaemic women. METHODS/DESIGN: The WOMAN-2 trial is an international, multicentre, randomised, double-blind, placebo-controlled trial to quantify the effects of TXA on postpartum bleeding in women with moderate or severe anaemia. Ten thousand women with moderate or severe anaemia who have given birth vaginally will be randomised to receive 1 g of TXA or matching placebo by intravenous injection immediately (within 15 min) after the umbilical cord is cut or clamped. The primary outcome is the proportion of women with a clinical diagnosis of primary PPH. The cause of PPH will be described. Data on maternal health and wellbeing, maternal blood loss and its consequences, and other health outcomes will be collected as secondary outcomes. The main analyses will be on an 'intention-to-treat' basis, irrespective of whether the allocated treatment was received. Results will be presented as appropriate effect estimates with a measure of precision (95% confidence intervals). Subgroup analyses will be based on the severity of anaemia (moderate versus severe) and type of labour (induced or augmented versus spontaneous). A study with 10,000 patients will have over 90% power to detect a 25% relative reduction from 10 to 7.5% in PPH. The trial will be conducted in hospitals in Africa and Asia. DISCUSSION: The WOMAN-2 trial should provide reliable evidence for the effects of TXA for preventing postpartum bleeding in women with anaemia. TRIAL REGISTRATION: ISRCTN, ISRCTN62396133 . Registered on 7 December 2017; ClincalTrials.gov, ID: NCT03475342 . Registered on 23 March 2018

Alternative routes for tranexamic acid treatment in obstetric bleeding (WOMAN-PharmacoTXA trial): a randomised trial and pharmacological study in caesarean section births.

OBJECTIVE: To examine the safety, efficacy and pharmacology of intravenous (IV), intramuscular (IM) and oral tranexamic acid (TXA) use in pregnant women. DESIGN: Randomised, open-label trial. SETTING: Hospitals in Pakistan and Zambia. POPULATION: Women giving birth by caesarean section. METHODS: Women were randomised to receive 1 g IV, 1 g IM, 4 g oral TXA or no TXA. Adverse events in women and neonates were recorded. TXA concentration in whole blood was measured and the concentrations over time were examined with population pharmacokinetics. The relationship between drug exposure and D-dimer was explored. The trial registration is NCT04274335. MAIN OUTCOME MEASURES: Concentration of TXA in maternal blood. RESULTS: Of the 120 women included in the randomised safety study, there were no serious maternal or neonatal adverse events. TXA concentrations in 755 maternal blood and 87 cord blood samples were described by a two-compartment model with one effect compartment linked by rate transfer constants. Maximum maternal concentrations were 46.9, 21.6 and 18.1 mg/L for IV, IM and oral administration, respectively, and 9.5, 7.9 and 9.1 mg/L in the neonates. The TXA response was modelled as an inhibitory effect on the D-dimer production rate. The half-maximal inhibitory concentration (IC50 ) was 7.5 mg/L and was achieved after 2.6, 6.4 and 47 minutes with IV, IM and oral administration of TXA, respectively. CONCLUSIONS: Both IM and oral TXA are well tolerated. Oral TXA took about 1 hour to reach minimum therapeutic concentrations and would not be suitable for emergency treatment. Intramuscular TXA inhibits fibrinolysis within 10 minutes and may be a suitable alternative to IV

Maternal anaemia and the risk of postpartum haemorrhage: a cohort analysis of data from the WOMAN-2 trial

Background: Worldwide, more than half a billion women of reproductive age are anaemic. Each year, about 70 000 women who give birth die from postpartum haemorrhage. Almost all deaths are in low-income or middle-income countries. We examined the association between anaemia and the risk of postpartum haemorrhage. Methods: We did a prospective cohort analysis of data from the World Maternal Antifibrinolytic-2 (WOMAN-2) trial. This trial enrols women with moderate or severe anaemia giving birth vaginally in hospitals in Pakistan, Nigeria, Tanzania, and Zambia. Hospitals in each country where anaemia in pregnancy is common were identified from a network established during previous obstetric trials. Women who were younger than 18 years without permission provided by a guardian, had a known tranexamic acid allergy, or developed postpartum haemorrhage before the umbilical cord was cut or clamped were excluded from the study. Prebirth haemoglobin, the exposure, was measured after hospital arrival and just before giving birth. Postpartum haemorrhage, the outcome, was defined in three ways: (1) clinical postpartum haemorrhage (estimated blood loss ≥500 mL or any blood loss sufficient to compromise haemodynamic stability); (2) WHO-defined postpartum haemorrhage (estimated blood loss of at least 500 mL); and (3) calculated postpartum haemorrhage (calculated estimated blood loss of ≥1000 mL). Calculated postpartum haemorrhage was estimated from the peripartum change in haemoglobin concentration and bodyweight. We used multivariable logistic regression to examine the association between haemoglobin and postpartum haemorrhage, adjusting for confounding factors. Findings: Of the 10 620 women recruited to the WOMAN-2 trial between Aug 24, 2019, and Nov 1, 2022, 10 561 (99·4%) had complete outcome data. 8751 (82·9%) of 10 561 women were recruited from hospitals in Pakistan, 837 (7·9%) from hospitals in Nigeria, 525 (5·0%) from hospitals in Tanzania, and 448 (4·2%) from hospitals in Zambia. The mean age was 27·1 years (SD 5·5) and mean prebirth haemoglobin was 80·7 g/L (11·8). Mean estimated blood loss was 301 mL (SD 183) for the 8791 (83·2%) women with moderate anaemia and 340 mL (288) for the 1770 (16·8%) women with severe anaemia. 742 (7·0%) women had clinical postpartum haemorrhage. The risk of clinical postpartum haemorrhage was 6·2% in women with moderate anaemia and 11·2% in women with severe anaemia. A 10 g/L reduction in prebirth haemoglobin increased the odds of clinical postpartum haemorrhage (adjusted odds ratio [aOR] 1·29 [95% CI 1·21–1·38]), WHO-defined postpartum haemorrhage (aOR 1·25 [1·16–1·36]), and calculated postpartum haemorrhage (aOR 1·23 [1·14–1·32]). 14 women died and 68 either died or had a near miss. Severe anaemia was associated with seven times higher odds of death or near miss (OR 7·25 [95% CI 4·45–11·80]) than was moderate anaemia. Interpretation: Anaemia is strongly associated with postpartum haemorrhage and the risk of death or near miss. Attention should be given to the prevention and treatment of anaemia in women of reproductive age. Funding: The WOMAN-2 trial is funded by Wellcome and the Bill & Melinda Gates Foundation

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Background Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. Methods In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Findings Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Interpretation Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. Funding London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

WOMAN-ETAC Dataset

The WOMAN trial is an international clinical trial to study the effect of tranexamic acid on death, hysterectomy and other maternal outcomes, in women with PPH.14. The trial tested whether tranexamic acid, a blood clot stabiliser discovered in Japan in the 1950’s, could become an essential tool for fighting excessive bleeding soon after giving birth. This condition, known as postpartum haemorrhage, is the number one cause of maternal death around the world, particularly in low and middle income countries. Dataset contains baseline and follow-up measurements for: D-dimer concentration (mg/L), Maximum lysis (%), Haemoglobin concentration (g/L), International normalized ratio (INR), Prothrombin time (seconds), Activated partial thromboplastin time (seconds), Fibrinogen concentration (g/L), Clotting time (seconds), Amplitude (firmness) at 5 minutes (mm), Amplitude at 10 minutes (mm), Clot lysis at 30 and 60 minutes (%), and Maximum clot firmness (mm). THE DATASET CAN BE DOWNLOADED FROM THE FREEBIRD PLATFORM AT https://ctu-app.lshtm.ac.uk/freebird/