FAQs

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The DMC Charter states that they will reveal the unblinded results to the Trial Steering Committee if, and only if, two conditions are satisfied: (1) the results provide proof beyond reasonable doubt that treatment is on balance either definitely harmful or definitely favourable for all, or for a particular category of, participants in terms of the major outcome; (2) The results would, if revealed, be expected to substantially change the prescribing patterns of doctors who are already familiar with any other trial results that exist. Exact criteria for 'proof beyond reasonable doubt' are not, and cannot be, specified by a purely mathematical stopping rule, but they are strongly influence by such rules.

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If a discharged woman is subsequently readmitted to hospital, has any untoward medical event, or is known to have died after she is discharged, this should be reported as an adverse event using the adverse event form, if it occurs within 42 days (6 weeks) of randomisation. An Adverse Event is defined in the Protocol as 'any untoward medical occurrence'. Please see the Protocol and the Manual of Operating Procedures for further details. All women randomised onto the trial will be given a patient alert card. The woman should be advised that she should;

• Carry the card with her for at least 6 weeks after her entry to the trial (the date will be written inside the card)
• Present the card to any healthcare provider she sees
• Advise her family that she is carrying the card so that in the unlikely event she is seriously ill they can present the card to the healthcare provider on her behalf

In addition, to alert all medical staff to the fact that a woman has been randomised to the trial, a Post Discharge Information Form is completed at the time of randomisation and placed in the woman's medical records.

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Adverse events to be reported will be limited to those NOT already listed as primary or secondary outcomes, yet, which might reasonably occur as a consequence of the trial drug. Events that are part of the natural history of the primary event of PPH or expected complications of PPH should not be reported as adverse events. For example, low blood pressure and tachycardia are expected consequences of PPH and would not need to be reported.

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Randomisation codes will be generated and secured by an independent statistical consultant from Sealed Envelope Ltd (UK). The randomisation list was produced using Stata version 10. Randomisations were balanced 1:1 in blocks of 8 (corresponding to a box of trial treatment packs) so that each box contains 4 packs of tranexamic acid and 4 of placebo in random order.
The codes will be made available to the drug packing company explicitly for the treatment packs to be created in accordance with the randomisation list. Eligibility will be determined from the routinely collected clinical information and no trial-specific tests are required. Women eligible for inclusion should be randomised to receive either active (tranexamic acid) or placebo (sodium chloride 0.9%) treatment and the trial treatment started as soon as possible.
Baseline information will be collected on the trial entry form and the lowest consecutively numbered pack will be taken from the box of eight treatment packs. At the point when the treatment ampoules in both dose packs are confirmed to be intact, the patient is considered to be randomised onto the trial. The entry form data will be sent to the Trial Coordinating Centre as soon as possible. Once randomised, the outcome of the woman should be obtained even if the trial treatment is interrupted or is not actually given.

A.

Although it is unlikely that breastfed babies will develop thromboembolic events, we are collecting the following information about the health status of the babies at the same time as the outcome of the mother, which is at 42 days from randomisation or at prior death, discharge or transfer
The information being collected is whether the baby is alive or dead and the presence of any thromboembolic event. This must be a confirmed diagnosis and may include any venous or arterial thrombosis (thrombosis of limb artery/deep veins, renal artery/veins, pulmonary embolism, hepatic veins, caval veins, intracardiac thrombosis, portal vein, mesenteric veins/artery, cerebral veins, retinal vein, ischemic stroke, arteries, aorta, myocardial infarction, microvascular thrombosis from purpura fulminans or disseminated intravascular coagulation).

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Yes. All randomised patients will be included in the analyses on an intention to treat basis, whether or not they received the full course of the trial treatment.

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The shipment worldwide of glass ampoules in which the trial drug is contained can be problematic because of breakage despite the best packaging. Using the approach where randomisation occurs when the treatment ampoules are confirmed as being intact avoids the investigator having to open all treatment packs in advance to confirm whether an ampoule is broken or not. Opening all treatment packs can cause problems as there is potentially a risk that the treatments can get mixed up.
It is unlikely that breakages will routinely happen at any one site. In the event of multiple breakages at any one site, this will be investigated fully to ensure that the randomisation process is not being compromised.
A randomisation approach with a fixed block size is being used as the sample size is relatively large. This approach is expected to achieve a balance between groups in size and other characteristics. In addition, a fixed block size will allow for better balance within trial sites.

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In addition to the Protocol, a detailed Manual of Operational Procedures for Investigators is provided. This document asks investigators to complete Questions 1-16 to assess eligibility. Question 17 is completed to document the consent process and Questions 18 - 21 completed at randomisation.

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The decision for surgery will be that of the doctor treating the woman. Inclusion of the woman in this trial will not alter that. As indicated in the Protocol and in the Investigator's Manual of Operating Procedures, women should receive ALL clinically indicated treatments (which may include surgery). There is no standard process for deciding when surgery is indicated and all investigators should follow their clinical judgement.

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No. There are no special storage temperature requirements for the trial treatment.

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Women with primary postpartum haemorrhage (within 24 hours of delivery) can be included providing that the responsible doctor is substantially uncertain as to the effectiveness of the trial treatment in the particular patient. Information on time from delivery will be collected so that sub-group analyses can be carried out to determine if the effect of the trial treatment varies according to time from delivery.

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The trial treatment should not be administered in the same intravenous line as either penicillin or blood. There are no other known interactions.

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In a large trial involving hundreds of hospitals internationally it is inevitable that there will be some differences in the management of labour between hospitals. However, these will not bias the trial results. Providing that the trial is large enough, randomisation will ensure that the intervention and control groups are identical with regard to both known and unknown confounders.
It is possible that the size of the intervention effect may vary a little bit depending on the type of management given; information will be collected on key aspects of patient management. Nevertheless, any differences would not affect the direction of the treatment effects. Patients in the future will almost certainly receive different forms of care than they do today. Treatments shown to be effective today may be more or less effective in the future, but the direction of the effect will be the same. Rather than standardise patient management, it is more important that the trials are large enough and the WOMAN Trial will be the largest study ever conducted in maternal haemorrhage.

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Patients are eligible for inclusion in the WOMAN Trial if they have a clinical diagnosis of PPH. Patients can be included if the doctor considers that there has been a blood loss of more than 500 ml after vaginal delivery or 1000 ml after caesarean, or if they consider that the blood loss is sufficient to compromise the haemodynamic status of the woman. It is entirely appropriate that trial entry is based on a clinical assessment of bleeding, since should the treatment be proven to be effective, this is how the treatment will be used. If the clinician's diagnosis of postpartum bleeding at a particular hospital is based on some standardised measure of blood loss, such as the use of calibrated drapes, then this may be used to guide trial entry. However, since there is no uniformly accepted method of assessing blood loss it would be inappropriate to insist on any particular approach in this trial as the trial is designed to assess the effect of tranexamic acid in the context of normal clinical practice.

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It is important to note that the trial drug is only administered after babies have been delivered, therefore the only exposure a baby would have to the trial drug is through breastfeeding. The ability of a woman to breastfeed while suffering postpartum haemorrhage will be significantly reduced. The trial treatment with tranexamic acid is only two doses within the first 24 hours after PPH is diagnosed Tranexamic acid is 90% eliminated within 24 hours of administration. According to the manufacturer's summary of product characteristics, the concentration of tranexamic acid that passes into breast milk is extremely low (approximately 100th of the concentration of maternal blood) and that an antifibrinolytic effect is unlikely. Although the risks from TXA to babies are relatively low in this trial, we believe that it is still appropriate to collect this information to provide the best evidence

A.

A clinical trial can only be reasonably conducted among clinicians who are uncertain about the effects of the trial treatment. For example, some doctors may decline to take part in the WOMAN trial because in that particular hospital they believe that tranexamic acid is effective and routinely use it in the management of PPH. Similarly, other hospitals may decline to take part because they believe that tranexamic acid is ineffective. The WOMAN trial, like any other clinical trial can only practicably be conducted among doctors who are uncertain as to the balance of benefits and harms. In the case of tranexamic acid, a great many doctors remain uncertain as to the balance of benefits and harms and hundreds have already applied to join the woman trial. Similarly, there may also be differences within hospitals such that some individual doctors are uncertain as to the balance of risk and benefits when others are convinced that the treatment is either useful or useless.
The use of the uncertainty principle does not present a threat to the internal validity of the trial. The trial result will be an unbiased estimate of the effect of the trial treatment within the trial population. The extent to which the results apply to other patients will always be a matter for judgement. The patient population included in the trial will be fully described so that doctors can make an informed judgment as to the extent to which they believe that the results of the trial would be applicable to particular women with PPH.

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The baseline event rate (the risk of death or hysterectomy after PPH) is likely to vary considerably between countries. Should the average baseline event rate turn out to be higher than was anticipated in our sample size calculation, then our study will have more statistical power than we have estimated. Our use of conservative baseline risk estimates for the sample size calculation is an important strength and not a weakness. We also agree that should TXA be shown to be effective then the clinical benefit will be greatest where the baseline risk is highest. Any proportionate reduction in the risk of death will save more lives where the risk of death is high than where the risk of death is low. We believe however that the most appropriate way to individualise the results from the WOMAN trial (to estimate the likely benefits and harms for a particular patient or group of patients) would be to apply the relative risk estimate from the trial as a whole to the baseline risk for the particular patient or group of patients. This would be more appropriate than conducting sub-group analyses which can be unreliable.

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Because it coincides with the usual date of postpartum follow-up and thus would provide sufficient comparable data.

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The trial treatment should be given as soon as the clinical diagnosis of PPH is made and the randomisation procedure completed. However, all patients should receive normal medical care whatever this may be.