01_The_WOMAN_Trial_Protocol_FINAL_v1.0_1_., Exams of Nursing

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Tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial CLINICAL TRIAL PROTOCOL Protocol Number: ISRCTN76912190 NUMBER DATE FINAL VERSION Version 1.0 11 May 2009 AMENDMENT (if any) TABLE OF CONTENTS Summary 1 Table of contents 3 1 INTRODUCTION 4 11 Need fora trial 5 12 Tranexamic acid and its effect on bleeding 5 13 Potential side effects of tranexamic acid 5 14 — Objective 6 2 TRIAL DESIGN 7 2.1 Overview: Pragmatic design and the uncertainty principle; Randomisation; Follow-up 7 2.2 Settings 7 23 Number of patients needed: Estimated event rate; Sample size and size of treatment effect 7 2.4 Recruitment of collaborating investigators 8 2.5 Eligibility: Inclusion criteria; Exclusion criteria; Eligibility graph 8 26 Consent and ethical considerations 9 27 Randomisation 11 28 Treatment 11 2.8.1 Dose selection 11 2.8.2 Drug manufacture, blinding and supply of trial treatment ny 2.8.3 Administration of trial treatment 12 2.8.4 Other treatments for PPH 12 29 Adverse Events 13 2.10 — Unblinding 14 2.11 Measures of outcome 14 2.12 Data collection 15 2.13 Monitoring 15 2.14 — End of trial for participants 16 2.15 Analysis 16 3 TRIAL ORGANISATION AND RESPONSIBILITIES 17 3.1 Sponsorship and trial management 7 3.2. Indemnity 7 3.3 Protocol Development 7 3.4 Independent Data Monitoring Committee 18 3.5 Trial Steering Committee 19 3.6 Collaborators’ responsibilities 19 3.7 Trial Management Group & Trial Coordinating Centre responsibilities 20 3.8 Contacting the TCC in an emergency 20 3.9 Publication & Dissemination of results 20 3.10 Financial support 21 4 ABBREVIATIONS USED 22 5 REFERENCES 23 6 APPENDICES 2 Appendix 1: Entry form 26 Appendix 2: Outcome form 28 Appendix 3: Country/site specific documents 30 a. _ Brief information leaflet for pregnant women & family 30 b. Consent procedure overview 31 c. Information sheet for woman and her representative 32 d. Informed consent form for woman 35, e. _ Informed consent form for representative 36 Page 3 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 2 1 INTRODUCTION Each year, worldwide, about 530,000 women die from causes related to pregnancy and childbirth. Nearly all (99%) of these deaths are in low and middle income countries.* Haemorrhage, which usually occurs in the postpartum period, is responsible for between one quarter and one third of obstetric deaths.” Postpartum haemorrhage (PPH) is commonly defined as blood loss of >500mL after vaginal delivery of a baby, or >1000mL after caesarean section. However, these thresholds do not take into account pre-existing health status, and blood loss of as little as 200mL can be life-threatening for a woman with severe anaemia or cardiac disease. Of the 14 million women who have PPH each year, about 2% die, with an average interval from onset of bleeding to death of 2 to 4 hours.” Although many deaths from PPH occur outside healthcare facilities, a significant number occur in hospital, where effective emergency care has the potential to save lives.** PPH is also an important cause of maternal mortality in high income countries, accounting for about 13% of maternal deaths.° PPH also causes hospital morbidity. Many women require blood transfusion which sometimes can transmit blood borne viral infections. Approximately 1% of women with spontaneous vaginal deliveries require transfusion, but the figure increases to 5% or 6% for women with instrumental deliveries or caesarean sections.’ The risk of infection from transfused blood is considerably higher in countries that do not screen all blood for transfusion.® In high income countries the risk of transfusion transmitted infection is low, but adverse reactions related to blood transfusion are common.® Severe anaemia is a common consequence of PPH and affects about 11% of the 14 million women with PPH each year.” Severe anaemia can cause disabling fatigue and seriously reduce a woman’s capacity to look after her children and to work.” Systemic antifibrinolytic agents are widely used in surgery to prevent clot breakdown (fibrinolysis) in order to reduce surgical blood loss. A systematic review of randomised controlled trials of antifibrinolytic agents in surgical patients identified 211 randomised controlled trials including 20,781 randomised participants. The results show that tranexamic acid (TXA) reduces the risk of blood transfusion by a relative 39% (RR=0.61, 95%CI 0.54 to 0.69). In all patients, TXA reduces transfused volume by 1.1 units (95%CI 0.64 to 1.59). TXA may also reduce the need for re- operation due to bleeding (RR=0.67, 95%CI 0.41 to 1.09). There was no evidence of an increased risk of thrombotic events.” TXA significantly reduces uterine blood loss in women with menorrhagia and is “recommended for consideration” as a treatment in intractable postpartum haemorrhage in the UK."° However, at present there is little reliable evidence from randomised trials on the effectiveness of TXA in the treatment of PPH. A systematic review of randomised trials of TXA in PPH conducted by the investigators identified three trials of the prophylactic use of TXA, including a total of 460 participants.”° Although there was a statistically significant reduction in average postpartum blood loss in women treated with TXA [weighted mean reduction of approximately 100 mL] the quality of the trials was poor. None had adequate allocation concealment and even in aggregate the trials were too small to assess the effects of TXA on the clinically important end points of mortality, hysterectomy and thrombotic side effects. The most recently updated PPH treatment guidelines prepared by the World Health Organization (WHO) state that TXA may be used in the treatment of PPH if other measures fail, but points out that the quality of evidence on which this recommendation is based is low and recommends that further clinical trials of TXA in PPH are conducted. Page 4 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 1.1 NEED FOR ATRIAL The WOMAN Trial will provide a reliable scientific basis for recommendations as to whether or not tranexamic acid should be used in the treatment of PPH. If TXA reduces mortality in women with PPH, this would be of considerable significance worldwide. There is a global commitment to the Millennium Development Goal (MDG) of reducing maternal deaths by three-quarters by the year 2015, a commitment that requires a reduction of the maternal mortality ratio by 5.5% each year. Because maternal haemorrhage accounts for over a quarter of deaths, an effective treatment for PPH would contribute importantly to the MDG of reducing maternal mortality. TXA might also reduce the need for hysterectomy, decrease the risk of anaemia and avoid the need for blood transfusion. Blood is a scarce resource in many countries with a risk of transfusion transmitted infections. If TXA was effective in the hospital setting, further research could be conducted to evaluate its use in the community, possibly including the use of oral rather than intravenous administration. The results of this trial will be disseminated by publication in peer reviewed medical journals, conference presentations, and in an updated version of the Cochrane systematic review of treatments for postpartum bleeding. There is evidence that hospitals participating in multi-centre trials are more likely to implement the trial results.”* For this reason, a large international multi-centre trial like the WOMAN trial can be expected to have a substantial impact on clinical practice. The large network of collaborating sites will ensure that the results are disseminated worldwide. 1.2. TRANEXAMIC ACID AND ITS EFFECT ON BLEEDING In the haemostatic process, coagulation occurs rapidly at the site of a damaged vessel building a tight net of fibrin, while at the same time, the fibrinolytic system removes the fibrin deposits that could cause permanent vascular occlusion once vascular repair has taken place.”” The coagulation and fibrinolytic system are believed to be in a state of dynamic balance which maintains an intact vascular system. Tranexamic acid is a potent antifibrinolytic agent that exerts its effect by blocking lysine binding sites on plasminogen molecules and has the potential to enhance the effectiveness of the patient’s own haemostatic mechanisms. Consequently, clot breakdown (fibrinolysis) is inhibited and excessive or recurrent bleeding is reduced. During delivery, when the placenta separates from the uterine wall, a sequence of physiologic and haemostatic changes occur that reduce bleeding: strong myometrial contractions, increased platelet activity, a massive release of coagulant factors and a parallel increase in the fibrinolytic activity.”* As a result, there is a theoretical rationale for the use of antifibrinolytic agents in the treatment of postpartum haemorrhage.®**> 1.3. POTENTIAL SIDE EFFECTS OF TRANEXAMIC ACID As TXA inhibits the breakdown of fibrin deposits already formed, it might theoretically increase the risk of thromboembolism. However, the systematic review of TXA in surgery did not show statistically significant increases in the risks of any of the thromboembolic events assessed."* Page 5 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 United Kingdom to 2% in Nigeria or 14% in Congo-Brazzaville. Based on these ranges, a baseline event rate of 2.5% for mortality and 2.5% for hysterectomy might reasonably be expected. Sample size and size of treatment effect that should be detectable: Assuming a control group event rate of 2.5% for mortality and 2.5% for hysterectomy with 1% of women having both a hysterectomy and then dying, a study with 15,000 women would have over 90% power (two sided alpha=5%) to detect a clinically important 25% reduction from 4% to 3% in the primary endpoint of mortality or hysterectomy. A survey of baseline event rates among hospitals that have expressed interest in taking part shows that baseline event rates of this magnitude are realistic and that higher baseline event rates might reasonably be expected. Experience from the CRASH-1 and CRASH-2 clinical trials suggests that the anticipated rates of loss to follow-up (less than 1%) would not impact importantly on study power. 2.4 RECRUITMENT OF COLLABORATING INVESTIGATORS The trial will recruit collaborating sites from all countries worldwide and will continue to add sites to ensure the sample size is achieved. Suitable collaborating sites and investigators will be assessed on the level of obstetric service they provide and their ability to conduct the trial. In advance of the trial starting at a site the Principal Investigator must agree to adhere to Good Clinical Practice Guidelines and all relevant regulations in their country. In addition, all relevant regulatory and ethics approvals will need to be in place. 2.5 ELIGIBILITY Immediately after delivery of the baby/ies, all usual care should be given for the prevention of PPH. Some bleeding is expected after delivery. However, if bleeding continues and a diagnosis of PPH is made, all usual treatments should be given and at the same time the assessment for inclusion in the trial should be made. It is important to consider inclusion as early as possible. Inclusion criteria: All legally adult women with clinically diagnosed postpartum haemorrhage following vaginal delivery of a baby or caesarean section; women may have delivered their babies at a participating hospital or outside a participating hospital, with hospital admission following delivery: e where the responsible clinician is substantially uncertain as to whether or not to use TXA e when consent has been given according to approved procedures The clinical diagnosis of PPH may be based on any of the following: © estimated blood loss after vaginal delivery of a baby > 500 mL OR e >1000 mL from caesarean section OR e — estimated blood loss enough to compromise the haemodynamic status of the woman Exclusion criteria: e Women for whom the responsible clinician considers there is a clear indication for TXA should not be randomised. e Women for whom the responsible clinician considers there is a clear contraindication for TXA should not be randomised (e.g. a known thromboembolic event during pregnancy). The fundamental eligibility criterion is the responsible clinician’s ‘uncertainty’ as to whether or not to use an antifibrinolytic agent in a particular woman with postpartum haemorrhage. Page 8 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 The TXA summary of product characteristics’ and an Investigator’s Brochure will be provided to investigators to ensure they have adequate information when considering the risk-benefit and the appropriateness of the trial for each woman. Graph 1: Eligibility POTENTIALLY ELIGIBLE All adult women whe are clinically diagnosed with postpartum haemorrhage following vaginal delivery or caesarean section CLINICIAN IS “REASONABLY CER IAIN” CLINICIAN IS “REASONABLY CERIAIN™ THAT ANTIFIBRINOLYTIC AGENTS THAT ANTIFIBRINOiYTIC AGENTS ARE INDICATED ARE CONTRA-INDICATED INELIGIBLE INELIGIBLE GIVE ANTIFIBRINOLYTIC AGENTS; DO NOT GIVE ANTIFIBRINOLYTIC AGENTS; DO NOT RANDOMISE DO NOT RANDOMISE elite rane “SUBSTANTIALLY UNCERTAIN” as to the appropriateness of antifibrinolytic agents in this woman RANDOMISE TRANEXAMIC AclIn<” D> PLACEBO 2.6 CONSENT AND ETHICAL CONSIDERATIONS This trial will be carried out worldwide and will include women soon after delivery of a baby. Postpartum haemorrhage is an emergency situation and clinical activities will be directed towards the provision of emergency care. Eligible women have a life threatening condition. Furthermore, their physical, mental and emotional state may be altered as a result of their blood loss or labour pains or by drugs administered during the labour. The consent process in this situation requires careful consideration bearing in mind applicable regulatory requirements, adherence to ICH-GCP and the requirements in the Declaration of Helsinki. Advance Information: The majority of women deliver without complications and it would not be in the best interest of all pregnant women to cause undue concern by providing detailed information about this trial in the antenatal/delivery period. Also, it is not possible to identify in advance those women who will go on to develop PPH, and obtain advance consent. Therefore, where possible, a summary of the trial information will be provided to Page 9 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 pregnant women (Appendix 3a). Refusal to be considered for participation will be documented in the woman’s medical records and her decision respected. Following delivery of her baby, and once a woman has been diagnosed with PPH, a critical clinical emergency situation exists. The risk of death is highest early after delivery. The process by which information will be given and consent obtained will depend on the need for urgent clinical intervention and her physical, mental and emotional state. Also, the availability and ability of a personal representative to make a decision on the woman’s behalf will have to be taken into consideration. The approach which will allow the woman to have the most input into the decision making process without endangering her life will be utilised: a) The woman is fully competent: The woman will be approached with the agreement of the primary carer (the midwife or doctor) at the time of diagnosis. Factors which may impair her decision making process including pain, altered level of consciousness due to drugs given and degree of blood loss, will be taken into consideration. An Information Sheet (Appendix 3c) will be provided and the study will be discussed with her and a written consent obtained (Appendix 3d). If the woman is unable to read or write, then the information sheet may be read to her and she may then mark the consent form with either a cross or thumbprint. In this event, a witness NOT associated with the trial, must provide a full signature confirming the mark. b) The woman’s mental capacity is impaired and either a Personal or Professional representative is available: Information should be given to the woman taking her level of mental impairment into consideration. Oral refusal by the woman should be respected and she should not be enrolled. a. If a Personal Representative (PeR) who is knowledgeable about the woman’s values and beliefs is available, an Information Sheet will be provided. Opportunity for questions should be given and written consent obtained. If the PeR is unable to read or write, then the information sheet may be read to him/her and a mark with either a cross or thumbprint made on the consent form. In this event, a witness NOT associated with the trial, must provide a full signature confirming the mark. b. Ifa Personal Representative is not available and the woman is unable to provide valid informed consent, then an independent doctor / midwife / other site staff allowed to fulfil this role (ideally the primary carer if s/he is not part of the trial team) may be asked to consent as a Professional Representative (PrR). Informed consent given by a representative shall represent the woman’s presumed will. c) The woman’s mental capacity is impaired and neither a Personal nor Professional representative is available: In situations where the woman is facing a clinical emergency and no PeR/PrR is available, the investigator and ONE independent person (doctor or midwife) who is not participating in this trial may enrol the woman into the trial by certifying in writing in the woman’s medical records that: e the woman is facing a life-threatening postpartum haemorrhage; e the woman is unable to give her consent as a result of her medical condition; e itis not feasible to contact the woman’s PeR/PrR to obtain consent within the window period; and e neither the woman nor the woman’s PeR/PrR nor any member of the family has informed the investigator of any objections to the woman being used as a participant in this trial. For women enrolled under such emergency consent procedure, the woman or her PeR or PrR should be informed about the trial as soon as it is possible and asked to consent for continuation of any trial procedure. A summary overview of the consent procedure is provided in Appendix 3b. The requirements of the relevant ethics committee will be adhered to at all times. Page 10 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 Tranexamic acid or placebo would be an additional treatment to the routine management of postpartum haemorrhage. 2.9 ADVERSE EVENTS (AEs) TXA has a well documented safety profile. No increase in thromboembolic risks associated with its use has been shown to date. However, as discussed in Section 1.3 an expected complication of pregnancy is an increased risk of thromboembolic events. This trial will collect data on all thromboembolic events as secondary outcomes, and all such events are routinely reported to the independent data monitoring committee (DMC) for unblinded review. Definitions: Adverse event (AE) Any untoward medical occurrence affecting a trial participant during the course of a clinical trial Serious Adverse Event (SAE) Aserious adverse event (experience) is any untoward medical occurrence that at any dose e results in death; eis life-threatening; e requires inpatient hospitalisation or prolongation of existing hospitalisation; e results in persistent or significant disability/incapacity; or © isa congenital anomaly/birth defect. Adverse Reaction (AR) An adverse event when there is at least a possibility that it is causally linked to a trial drug or intervention Serious Adverse Reaction (SAR) SAE that is thought to be causally linked to a trial drug or intervention Suspected Unexpected Serious Adverse Reaction (SUSAR) An unexpected occurrence of a SAR; there need only be an index of suspicion that the event is a previously unreported reaction to a trial drug or a previously reported but exaggerated or unexpectedly frequent adverse drug reaction. Reporting of Adverse Events for this trial: Death, life-threatening complications and prolonged hospital stay are pre- specified outcomes to be reported in this trial and also to the independent data monitoring committee. This clinical trial is being conducted in a critical emergency condition, using a drug in common use. It is important to consider the natural history of the critical medical event affecting each woman enrolled, the expected complications of this event and the relevance of the complications to TXA. Adverse events to be reported using an adverse event reporting form 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. In addition, if a woman is discharged from the randomising hospital before day 42 and is readmitted to hospital, requires medical care for any reason or is known to have died, an ‘adverse event form’ should be completed irrespective of the cause. Page 13 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 If a Serious Adverse Event occurs, this should be logged by calling the Trial Coordinating Centre Emergency Helpline and a written report submitted within 24 hours. The TCC will coordinate the reporting of all SAEs to all relevant Regulatory Agencies, Ethics Committees and local investigators as per local legal requirements. 2.10 UNBLINDING In general there should be no need to unblind the allocated treatment. If some contraindication to antifibrinolytic therapy develops after randomisation, e.g. clinical evidence of thrombosis, the trial treatment should simply be stopped and all usual standard care given. Unblinding should be done only in those rare cases when the clinician believes that clinical management depends importantly upon knowledge of whether the patient received antifibrinolytic or placebo. In those few cases when urgent unblinding is considered necessary, a 24-hour telephone service will be available and details provided in the Investigator’s Study File and wall posters. The caller will be told whether the patient received antifibrinolytic or placebo. An unblinding report form should be completed by the investigator. 2.11 MEASURES OF OUTCOME After a patient has been randomised, outcome in hospital will be collected even if the trial treatment is interrupted or is not actually given. No extra tests are required but a short single page Outcome Form will be completed 6 weeks (42 days) after randomisation, at discharge from the randomising hospital or at death (whichever occurs first). Primary Outcome: The primary outcome is the proportion of women who die or undergo hysterectomy. The primary cause of death will be described. Secondary outcomes: (a) Death (b) Surgical Interventions including hysterectomy; brace suture (B-Lynch/Cho); selective arterial embolisation; laparotomy for other reasons; manual removal of placenta; intrauterine tamponade (packing or gauzing the uterine cavity, condom-catheter, any other method of intrauterine tamponade); artery ligation, to achieve haemostasis. (c) Blood transfusion — blood or blood component units transfused (d Health Related Quality of life (HRQoL) will be measured by the proxy version of the EQ-5D at discharge from the randomising hospital or in hospital at 42 days after randomisation. The EQ-5D includes single item measures of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item is coded using 3 levels (1 = no problems; 2 = some problems; 3 = severe problems). The instrument includes a global rating of current health using a visual analogue scale (VAS) ranging from 0 (worst imaginable) to 100 (best imaginable). The EQ-5D isa generic measure of health status that provides a simple descriptive profile and a single index value that can be used in the clinical and economic evaluation of health care. (e) Thromboembolic events (myocardial infarction, strokes, pulmonary embolism, deep vein thrombosis) (f) Medical events including renal failure, Adult Respiratory Distress Syndrome, hypertensive disorders of pregnancy (including HELLP Syndrome, eclampsia, toxaemia of pregnancy) and other adverse events reported (g) Length of stay at hospital / time spent at an intensive care unit (h) Receipt of mechanical ventilation (i) Status of baby/ies: The health status of the baby/ies will be ascertained and information collected on any thromboembolic events in breastfed babies Page 14 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 (j) Cost-effectiveness analysis: An economic analysis will be relevant if TXA clearly demonstrates efficacy in achieving its clinical aims. In this case, the study will be undertaken in the form of a cost-effectiveness analysis with the aim of estimating the incremental cost-effectiveness ratio comparing the use of TXA with normal clinical practice. Analysis will be based on adjusted life years gained. A further analysis will explore the use of the EQ-5D data to quality adjust survival. In this study, the economic analysis is clearly bounded as virtually all significant resource use will occur in the initial period of hospitalisation. As such, neither a long-term resource analysis nor an analysis of out of hospital costs will be required. The trial use of TXA is likely to mirror its use in normal clinical practice, hence the cost-effectiveness estimated in the trial (adjusted for protocol driven costs) will closely approximate cost-effectiveness in actual clinical practice. Data on physical resource consumption (e.g. length and nature of hospital stay) will be collected for each patient and a common unit cost at a country level will be applied. A sensitivity analysis will be undertaken to assess the robustness of the economic analysis in response to variations in key variables such as drug prices. In all cases, the economic analysis will be integrated with the clinical trial procedures to optimise efficiency and minimise inconvenience to patients. 2.12 DATA COLLECTION This trial will be coordinated from LSHTM and conducted in hospitals in low, middle and high income countries. Most recruitment will be in countries with high rates of mortality and morbidity from postpartum haemorrhage. Data will be collected at each site by local investigators and transmitted to the TCC. Only data outlined on the entry, outcome and adverse event forms will be collected for this trial. Relevant data on an entry form will be collected before randomisation to assess eligibility and the form completed if randomised. The outcome form should be completed at death, discharge from the randomising hospital or 6 weeks (42 days) after randomisation whichever occurs first. This data should be collected from the woman’s and her baby/ies routine medical records as no special tests are required. If the woman (or her PeR or PrR) withdraws a previously given informed consent or refuses to consent for continuation in the trial, or if the woman dies and no consent is available from either a PeR/PrR, her data will be handled as follows: e Data collected to the point of withdrawal of consent will be used as part of the intention to treat analysis e Allrelevant adverse events identified will be reported as required to all relevant authorities To allow for variation in available technology for data transfer a variety of methods will be used in this trial. Data will be collected by the investigator on paper case report forms (CRFs) and transmitted to the TCC either as a paper form (by fax or email) or by entering the data directly into the trial database. Data can also be transmitted by entry onto electronic data files which can be emailed or uploaded to the TCC secure web server. In cases where electronic data files are used, data stored on the investigator’s computer(s) and data during transfer will be secured by encryption. The data will be used in accordance with local law and ethics committee approval. 2.13 MONITORING GCP section 5.18.3 states in regard to monitoring, “The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size and endpoints of the trial. In general there is a need for on-site monitoring, before, during, and after the trial; however in exceptional circumstances the sponsor may determine that central monitoring in conjunction with procedures such as investigators training and meetings, and extensive written guidance can assure appropriate conduct of the trial in accordance with GCP. Statistically controlled sampling may be an acceptable method for selecting the data to be verified.” Page 15 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 3.4 INDEPENDENT DATA MONITORING COMMITTEE (DMC) Membership: NAME AFFILIATION EXPERTISE Large scale randomised controlled trials; Professor Sir lain Chalmers James Lind Initiative, Oxford, UK Obstetric care Professor of Obstetrics & Gynaecology; . . Convenor, Thai Cochrane Network; . Professor Pisake Lumbiganon Obstetric care Faculty of Medicine, Khon Kaen University, Thailand Statistician (Extensive experience of Dr Gilda Piaggio Statistika Consultoria, Sao Paulo, Brazil reproductive health and research at the World Health Organization) Mortality and severe morbidity is expected within the target population. To provide protection for study participants, an independent DMC has been appointed for this trial to oversee the safety monitoring. The DMC will review on a regular basis accumulating data from the ongoing trial and advise the Trial Steering Committee regarding the continuing safety of current participants and those yet to be recruited, as well as reviewing the validity and scientific merit of the trial. The DMC composition, name, title and address of the chairman and of each member, will be given in the DMC Charter which will be in line with that proposed by the DAMOCLES Study Group. Membership includes expertise in the relevant field of study, statistics and research study design. The DMC Charter includes, but is not limited to, defining: (a) the schedule and format of the DMC meetings (b) the format for presentation of data (c) the method and timing of providing interim reports (d) stopping rules Standard Operating Procedures: The Data Monitoring Committee (DMC) has the responsibility for deciding whether, while randomisation is in progress, the unblinded results (or the unblinded results for a particular subgroup), should be revealed to the TSC. The DMC Charter states that they will do this 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, if revealed, would be expected to substantially change the prescribing patterns of clinicians 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 influenced by such rules. DMC Charter is in agreement with the Peto-Haybittle**” stopping rule whereby an interim analysis of major endpoint would generally need to involve a difference between treatment and control of at least three standard errors to justify premature disclosure. An interim subgroup analysis would, of course, have to be even more extreme to justify disclosure. This rule has the advantage that the exact number and timing of interim analyses need not be pre-specified. In summary, the stopping rules require extreme differences to justify premature disclosure and involve an appropriate combination of mathematical stopping rules and scientific judgment. Page 18 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 3.5 TRIAL STEERING COMMITTEE Membership: NAME AFFILIATION EXPERTISE Professor Adrian Grant (Chair) Director, Health Services Research Unit, University of Aberdeen Health Services Research; Randomised Control Trials Professor lan Roberts (Principal Investigator) London School of Hygiene & Tropical Medicine Epidemiology; Randomised Control Trials; Conduct of large scale international trials Dr Metin Giilmezoglu Dr Metin Giilmezoglu World Health Organization, Geneva Obstetrician; Co-ordinating Editor of the WHO Reproductive Health Library; Randomised Control Trials Dr Kaosar Afsana BRAC Health Programme, Bangladesh Reproductive & Sexual Health & Rights; Rural and Urban Maternal, Neonatal and Child Health Programme in BRAC Dr Oladapo Olayemi University College Hospital, Ibadan, Nigeria Consultant Obstetrician; perspective on obstetrics in a developing country Professor Beverley Hunt Kings College, London Professor of Thrombosis & Haemostasis, Randomised Control Trials The role of the Trial Steering Committee (TSC) is to provide overall supervision of the trial. In particular, the TSC will concentrate on the progress of the trial, adherence to the protocol, patient safety and consideration of new information. The TSC must be in agreement with the final Protocol and, throughout the trial, will take responsibility for: (a) major decisions such as a need to change the protocol for any reason (b) monitoring and supervising the progress of the trial (c) reviewing relevant information from other sources (d) considering recommendations from the DMC (e) informing and advising the Trial Management Group on all aspects of the trial The steering committee consists of experienced obstetric experts, clinical trialists as well as a Reproductive & Sexual Health & Rights representative. Face to face meetings will be held at regular intervals determined by need, but no less than once a year. A TSC Charter will be agreed at the first meeting which will detail how it will conduct its business. When outcome data are available for 1,000 trial participants, the TSC will review the rate of recruitment into the trial and the overall event rates. The TSC will consider the extent to which the rate of recruitment and the event rates correspond to those anticipated before the trial and will take whatever action is needed in light of this information. 3.6 COLLABORATORS’ RESPONSIBILITIES Coordination within each participating hospital will be through a local Principal Investigator whose responsibility will be detailed in an agreement in advance of starting the trial and will include: e Ensure all necessary approvals are in place prior to starting the trial e Delegate trial related responsibilities only to suitably trained and qualified personnel e Train relevant medical and nursing staff who see obstetric patients and ensure that they remain aware of the state of the current knowledge, the trial and its procedures (there are wall charts, pocket summaries and a set of slides to assist with this) e Agree to comply with the final trial protocol and any relevant amendments e — Ensure that all women with postpartum haemorrhage are considered promptly for the trial Page 19 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 e — Ensure consent is obtained in line with local approved procedures e — Ensure that the patient entry and outcome data are completed and transmitted to the TCC in a timely manner e Ensure the Investigator’s Study File is up-to-date and complete e — Ensure all Adverse Events are reported promptly to the TCC e Accountability for trial treatments at their site e — Ensure the trial is conducted in accordance with ICH GCP and fulfils all national and local regulatory requirements e Allow access to source data for monitoring, audit and inspection e Be responsible for archiving all original trial documents including the data forms for five years after the end of the trial 3.7. TRIAL MANAGEMENT GROUP (TMG) AND TRIAL COORDINATING CENTRE (TCC) RESPONSIBILITIES e The Trial Management Group will consist of the Protocol Committee members (Section 3.3) plus a trial manager, data manager and trial administrator. e The TCC will act on behalf of the Sponsor and will be responsible to the TMG to ensure that all Sponsor's responsibilities are carried out. The responsibilities will include (but not limited to): Report to the Trial Steering Committee Maintain the Trial Master File Identify trial sites Confirm all approvals are in place before release of the trial treatment and the start of the trial at a site Provide training about the trial Provide study materials Data management centre 24-hour advice and unblinding service Give collaborators regular information about the progress of the study Respond to any questions (e.g. from collaborators) about the trial Ensure data security and quality and observe data protection laws Safety reporting Ensure trial is conducted in accordance with the ICH GCP Statistical analysis 0000000000000 00 Publication of trial results 3.8 CONTACTING THE TCC IN AN EMERGENCY For urgent enquiries, adverse event reporting and unblinding queries investigators can contact the 24-hour telephone service provided by the TCC. Acentral telephone number is given in the Investigator’s Study File and posters. 3.9 PUBLICATION AND DISSEMINATION OF RESULTS All efforts will be made to ensure that the trial protocol and results arising from the WOMAN trial are published in an established peer-reviewed journal. At least one publication of the main trial results will be made. All publications will follow relevant external guidance such as the ‘Uniform Requirements for Submission of Manuscripts to Biomedical Journals’ issued by the International Committee of Medical Journal Editors (ICMJE) (2008 update) and the CONSORT statement.*°*” Links to the publication will be provided in all applicable trial registers. Dissemination of results to patients will take place via the media, trial website ([email protected]) and relevant patient organisations. Collaborating investigators will play a vital role in disseminating the results to colleagues and patients. Page 20 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 5 REFERENCES 1. World Health Organization UNCF, United Nations Population Fund, World Bank. Maternal Mortality in 2005. Estimates developed by WHO, UNICEF, UNFPA, and The World Bank. Geneva. Edited by the World Health Organisation. Available from: http://www.who.int/reproductive-health/publications/maternal_mortality 2005/mme_2005.pdf., (Accessed 11 May 2009). 2. AbouZahr C. Antepartum and Postpartum Haemorrhage. Health Dimensions of Sex and Reproduction. 1st edition. Edited by Murray, J Lopez, A. Boston. Harvard School of Public Health on behalf of the World Health Organisation and the World Bank, 1998: 165-187. 3. Lalonde A, Daviss BA, Acosta A, Herschderfer K. Postpartum hemorrhage today: ICM/FIGO initiative 2004-2006. Int J Gynaecol Obstet 2006;94(3):243-53. 4. Ronsmans C, Graham WJ. Maternal mortality: who, when, where, and why. Lancet 2006;368(9542):1189-200. 5. Kongnyuy EJ, Mlava G, van den Broek N. Facility-based maternal death review in three districts in the central region of Malawi: an analysis of causes and characteristics of maternal deaths. Womens Health Issues 2009;19(1):14-20. 6. Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF. WHO analysis of causes of maternal death: a systematic review. Lancet 2006;367(9516):1066-74. 7. Ekeroma AJ, Ansari A, Stirrat GM. Blood transfusion in obstetrics and gynaecology. Br J Obstet Gynaecol 1997;104(3):278-84. 8. World Health Organisation. Global Database on Blood Safety. Edited by WHO. Geneva., 2001-2002: 1-32. 9. Taylor C, Cohen H, Jones H, Asher D, Brant L, Chapman C, Davies T, Gray A, Milkins C, Norfolk D, Tinegate H. Serious Hazards of Transfusion Annual Report 2007. Edited by SHoTS Commitee. London (UK); 2008., 2007. 10. AbouZahr C. Global burden of maternal death and disability. Br Med Bull 2003;67:1-11. 11. World Health Organization. The prevalence of anaemia in women: a tabulation of available information. WHO/MCH/MSM/92.2. http://whqlibdoc.who.int/hq/1992/ (WHO_MCH_MSM_92.2.pdf), 1992. 12. Mousa HA, Alfirevic Z. Treatment for primary postpartum haemorrhage. Cochrane Database Syst Rev 2007(1):CD003249. 13. Nayama M, Moulaye AA, Djibrill B, Garba M, Idi N, Boukerrou M. [Haemostatic hysterectomies in developing countries: A vital act. Prospective study in a reference Nigerian maternity]. Gyneco/ Obstet Fertil 2006;34(10):900-5. 14. Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, McClelland B, Laupacis A, Fergusson D. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2007(4):CD001886. 15. WHO Recommendations for the prevention of postpartum haemorrhage. Geneva: World Health Organisation, 2007. 16. Prendiville WJ, Elbourne D, McDonald S. Active versus expectant management in the third stage of labour. Cochrane Database Syst Rev 2000(2):CD000007. 17. Gulmezoglu AM, Villar J, Ngoc NT, Piaggio G, Carroli G, Adetoro L, Abdel-Aleem H, Cheng L, Hofmeyr G, Lumbiganon P, Unger C, Prendiville W, Pinol A, Elbourne D, El-Refaey H, Schulz K. WHO multicentre randomised trial of misoprostol in the management of the third stage of labour. Lancet 2001;358(9283):689-95. 18. Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indications. Drugs 1999;57(6):1005-32. Page 23 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 19. National Collaborating Centre for Womens and Childrens Health. Intrapartum care of healthy women and their babies during childbirth. Clinical Guidance. RCGO Press, September 2007. 20. Ferrer PR, |. Sydenham, E. Blackhall, K. Shakur, H. Anti-Fibrinolytic Agents in Obstetric Haemorrhage: A Systematic Review. BMC Pregnancy Childbirth manuscript ID 4090955672420008 Submitted. 21. Ketley D, Woods KL. Impact of clinical trials on clinical practice: example of thrombolysis for acute myocardial infarction. Lancet 1993;342(8876):891-4. 22. Prentice CR. Basis of antifibrinolytic therapy. J Clin Pathol Suppl (R Coll Pathol) 1980;14:35-40. 23. Hellgren M. Hemostasis during normal pregnancy and puerperium. Semin Thromb Hemost 2003;29(2):125-30. 24. Bonnar J, Guillebaud J, Kasonde JM, Sheppard BL. Clinical applications of fibrinolytic inhibition in gynaecology. J Clin Pathol Suppl (R Coll Pathol) 1980;14:55-9. 25. Bolte AC, Bouma L, van Geijn HP. Medical therapies for primary postpartum hemorrhage. International Congress Series. Gynaecology, Obstetrics, and Reproductive Medicine in Daily Practice 2005;1279:364-368. 26. Gherman RB, Goodwin TM, Leung B, Byrne JD, Hethumumi R, Montoro M. Incidence, clinical characteristics, and timing of objectively diagnosed venous thromboembolism during pregnancy. Obstet Gynecol 1999;94(5 Pt 1):730-4. 27. Lindqvist P, Dahlback B, Marsal K. Thrombotic risk during pregnancy: a population study. Obstet Gynecol 1999;94(4):595-9. 28. Toglia MR, Weg JG. Venous thromboembolism during pregnancy. N Engl J Med 1996;335(2):108-14. 29. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ, 3rd. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143(10):697-706. 30. Summary of Product Characteristics for Cyklokapron. http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=1489 (accessed 11" May, 2009). 31. Peto R, Baigent C. Trials: the next 50 years. Large scale randomised evidence of moderate benefits. Bmj 1998;317(7167):1170-1. 32. Horrow JC, Van Riper DF, Strong MD, Grunewald KE, Parmet JL. The dose-response relationship of tranexamic acid. Anesthesiology 1995;82(2):383-92. 33. DAMOCLES Study Group. A proposed charter for clinical trial data monitoring committees: helping them to do their job well. Lancet 2005;365(9460):711-22. 34. Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol 1971;44(526):793-7. 35. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. Il. analysis and examples. Br J Cancer 1977;35(1):1-39. 36. Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication (Updated October 2008). (Accessed at http://www. icmje.org/ on 11" May, 2009). 37. Moher D, Schulz KF, Altman DG. The CONSORT statement: Revised Recommendations For Improving the Quality of Reports of Parallel-Group Randomized Trials. Lancet 2001; 357(9263):1191-1194. Page 24 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 6 APPENDICES Appendix 1: Entry form Appendix 2: Outcome form Appendix 3: Country/site specific documents a) b) ¢) a) e) Brief information leaflet for pregnant women & family Consent procedure overview Information sheet for woman and her representative Informed consent form for woman Informed consent form for representative Version 1.0 Page 25 of 36 Protocol ISRCTN76912190 Version date: 11 May 2009 APPENDIX 2 - OUTCOME FORM (page 1) Attach treatment pack sticker here or write box/pack number below: OUTCOME FORM an COMPLETE AT DISCHARGE FROM THE RANDOMISING HOSPITAL, NAMELESS” DEATH IN HOSPITAL OR 42 DAYS AFTER RANDOMISATION, WHICHEVER OCCURS FIRST_{| / LT] 1. HOSPITAL CODE ‘ 2. PATIENT a) Patient initials |__b) Patient hospital 1D number | ¢) Date of birth av (oo) | Monnet (ant | vena (rer) | d) If not known, estimated age | 3. OUTCOME 3.1 DEATH IN HOSPITAL 3.2 WOMAN ALIVE a) Date of death a) Discharged home - Date of discharge bay (00) woven () veas (ro) oar(oo} woven (ar) vean rev) b) Primary Cause of death (tick one option) b) Transferred to another hospital - Date of transfer Ll bteeding sey sua) ven re Cpuimonary embolism ) is hospital now (42 doys after randomisation) - Date Dlotnerdescrive here: = aro) over (a vernon) 3.3 IF ALIVE (at 42 days or prior discharge): £Q-5D Questions as follows, to be rated by the Doctor/tldwife based on their knowledge of the woman. Read instructions overleaf before completing. a) MOBILITY b) SELF-CARE c) USUAL ACTIVITIES (e.g. care for baby, work, study, housework, family or [Jo problems in walking about | [_]no problems with self-care leisure activities) [some problems in walking about | [-]some problems with washing ordressing | L]no problems with performing usual activities confined to bed [unable to wash or dress (some problems with performing usual activities Dlunable to perform usual activities d) PAIN / DISCOMFORT e) ANXIETY / DEPRESSION f) VALUE RECORDED ON VISUAL ANALOGUE SCALE (see reverse) no pain or discomfort C1 not anxious or depressed Li moderate pain ordiscomfart | [-] moderately anxious or depressed [extreme pain or discomfort Dlextremely anxious or depressed 4. MANAGEMENT a) DAYS IN INTENSIVE CARE UNIT 6. OTHER TREATMENTS FOR PPH a) BLOOD PRODUCTS TRANSFUSION ves | No (ifn0 ICU or not admitted to ICU, write ‘0’ here) (transfused in 42 days) (part unit = 1unit) b) MANAGEMENT (Circle one box on every line) Units whole blood/packed cells units Hysterectomy YES NO Fresh frozen plasma units Manual removal of placenta YES NO Other blood products units Intrauterine tamponade ves NO b) UTEROTONICS ADMINISTERED (after PPH aiagnosed)| y< No {Giclee box on every line) Embolisation YES NO Oxytocin, ves | NO Laparotomy for other reasons YES NO Ergometrine YES NO Brace sutures of the uterus YES NO. ‘Misoprostol ves | NO Artery ligation YES. No Prostaglandins (injectable) YES NO Mechanical ventilation _ (exclude use in general anaesthetic for surgery) om 7. TRIAL TREATMENT a) Dose 1 given NO 5. COMPLICATIONS (cice one box on every ine} | Dose Zgivan nO ve (please complete a separate form for each Pulmonary embolism s No 8. ABOUT THE BABY _| boty deiivered alive: Sections 1, 2 ond 8 only} Deep vein thrombosis YES No a) NEE E of live babies b) Ini ae of baby from this pregnancy con this form Stroke YES NO c) THIS BABY (Circle one box on each line) Myocardial infarction YES No Alive NO Renal failure YES NO Healthy NO Cardiac failure Yes NO Any confirmed thromboembolic event? YES NO Respiratory failure YES NO Breastfed at anytime after randomisation? NO etal THE i Hepatic failure ves | NO 9, PERSON COMPLETING FORM | ta parsconmney Sepsis YES No a) Name Seizure YES NO b) Position c) Signature SEE GUIDANCE NOTES ON REVERSE d) Date ar(io) mon (u rean fret) Protocol Code: ISRCTN76912190 Page 1of2 FINAL Version 1.0_OUTCOME FORM Page 28 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 APPENDIX 2 - OUTCOME FORM (page 2) DETAILED GUIDANCE ABOUT COMPLETING THIS FORM CAN BE FOUND IN YOUR INVESTIGATORS SECTION 3.3: EQ-5D° INSTRUCTIONS THIS SECTION OF THE OUTCOME FORM IS TO BE COMPLETED BY A DOCTOR/MIDWIFE WHO HAS PERSONAL KNOWLEDGE OF THE WOMAN. THE Please follow the EQ-5D guidance on the right. SECTION 8 If more than one baby delivered alive from this pregnancy, please complete Sections 1,2 and8 ona separate outcome form for each baby. Remember to write the randomisation number in the box on the top right hand corner of each form. HOW TO SEND Please see detailed guidance in your investigators study file AFTER COMPLETING THIS PAPER FORM, YOU CAN: Enter these data directly into the trial database (username and password required) e www. thewomantrial.Lshtm.ac.uk 4 Complete an Electronic Data Form (EDF) and send by email or upload to the trial intranet at www. thewomantrial.Lshtm.ac.uk * Send as a secure scanned document by email to [email protected] Fax to +44 20 7299 4663 STORE THIS ORIGINAL FORM IN YOUR SITEFILE STUDY FILE RESPONSE YOU GIVE SHOULD BE YOUR PERSPECTIVE OF THIS WOMAN’S STATUS COMPARED TO A NORMAL WOMAN POSTPARTUM. SECTION 3.3 Questions a-e: By placing a tick in one box in each group, please indicate which statement best describes this woman’s health state today. Do not tick more than one box in each group. Question f: To help people say how good or bad a health state is, we have drawn a scale (rather like a thermometer) below on which the best state you can imagine is marked 100 and the worst state you can imagine is marked 0. We would like you to indicate on this scale how good or bad the woman’s health is today, in your opinion. Please do this by drawing a line from the black text box below to whichever point on the scale indicates how good or bad you think the woman’s health is today. Record the value on the reverse. beset imagraple beat stale 100 BUSES Lely z ON ey fo today £ ° Worst imagnable © 1990 EuroQol Group’ and 'EQ-5D™ is a trademark of the EuroQol Group Protocol Code: ISRCTN76912190 Page 2 of 2 FINAL Version 1.0_OUTCOME FORM Page 29 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 APPENDIX 3a Brief information leaflet for pregnant women & family This hospital, like many others in this country and around the world, is involved in a research study to try and find better ways of treating women who develop severe bleeding soon after having a baby. Thank you for taking time to read this leaflet. What is the Woman Trial about? The WOMAN trial is a study being done to see whether using a drug called tranexamic acid will help women with severe bleeding soon after having a baby (postpartum haemorrhage) by reducing the amount of blood lost and therefore preventing them becoming too ill, This study will involve about 15,000 women worldwide. As severe bleeding is not a common problem and it is not possible to predict in advance exactly who will develop this condition, we are giving this information to all pregnant women to inform them of our plans. What is Postpartum Haemorrhage? Most women who give birth have no problems during or after the delivery of their baby. Following every birth there will be a small amount of bleeding from the mother ~ this is normal and usually nothing to worry about. However, occasionally after the baby is born there is much more bleeding, This extra bleeding is called postpartum haemorrhage (PPH). When this happens the doctors, nurses and midwives will do everything they can to stop the bleeding, because if too much blood is, lost the mother may become very il What causes Postpartum Haemorthage? Once a baby Is delivered, the womb (uterus) normally continues to contract (tightening of muscles of the uterus) and this expels the placenta, After the placenta is expelled, these contractions help compress the bleeding vessels in the area where the placenta was attached. If the uterus does not contract strongly enough, these blood vessels bleed freely and haemorrhage occurs. There are many other causes of postpartum haemorthage but this is ‘the most common, What Is Tranexamic Acid and why use it? ‘Tranexamic Acid (TXA) is a drug that is used to slow down and reduce bleeding. For example, it is often used when people go for major heart surgery to stop them losing too much blood. It Js also sometimes used for women who have very heavy periods. Because TXA is known to reduce blood loss in these situations, it is possible that if itis given to a woman with PPH, it may help to reduce the bleeding. But at the moment we do not know ifit will help for PH or not, What does the study involve? If a woman develops postpartum haemorrhage, the doctor will examine her, look at her medical records and decide whether she is suitable for the study, If she is suitable and well enough, the doctor will discuss the study with her and ask if she would be willing to take part in the WOMAN Trial. Otherwise her suitability for the trial will be discussed with her representative or the doctor/midwife primarily responsible for her, to see if she can join the trial If she does take part, she will receive an injection of either the TXA or a placebo (a liquid which does not contain TXA) directly into the vein. If after a while the bleeding still does not stop, the doctor may decide to give another injection of the TXA or placebo, After six weeks, or when the woman leaves hospital, the doctor or midwife will collect some more information from the medical records of the woman and her baby/ies to let the trial team know how she is getting on ‘Making a decision Please discuss this with family and friends and if you need more information the research team at this hospital will be happy to discuss the WOMAN trial with you. an 1a! Antifiorinolytic Tal PLEASE CONTACT: Name of doctor or miswite Address Telephone Email Women do not have to make a decision now about taking part in this study. This information sheet is to allow them to consider carefully their wishes in the event they are asked to take part. However, if after reading this and discussing it with others you feel that you definitely do NOT want to be involved in this study, please tell your doctor or midwife and ask them to make a note in your medical records. The study is organised by the London School of Hygiene & Tropical Medicine (University of London) and you can also contact them directly for information about the trial an 1a Antifibrinolytic Trial Website | www.womantral..shtm.acuk Tras Coordinating Ceatve, Room 160 London Schoo! of Hygiene & acres | Tropical Medicine Keppel Street, London WC1E 7HT Unites ingens Te +44(0)20 7299 4688 Fax +44(0)20 7299 4663 eal thewomantrial@tshtm 2¢.uk GENERAL INFORMATION LEAFLET ABOUT THE WOMAN TRIAL an World 1 Antifibinolytic Tia Please take a copy Version 1.0 Page 30 of 36 Protocol ISRCTN76912190 Version date: 11 May 2009 Information sheet for woman and her representative, page 2 3) Why have you been invited? You have been diagnosed with postpartum haemorrhage by your doctor. Your doctor has checked that you are suitable for the study, but it is up to you whether or not you decide to take part. 4) Who is doing the study and who can you call if you have any questions or problems? Dr is in charge of this study at this hospital. The study is coordinated by doctors and a trial team at The London School of Hygiene & Tropical Medicine (University of London). If you have any questions you can contact the doctor at: Address: Telephone: You are also free to visit the trial website to keep up to date with the progress of the trial: www.thewomantrial.Lshtm.ac.uk 5) A patient cannot be in this study if: e The doctor thinks there is a particular reason why tranexamic acid definitely should not be given e The doctor thinks there is a particular reason why tranexamic acid definitely should be given e They are not an adult 6) What will happen/has happened during this study? You will be given all the usual emergency treatments for severe bleeding after childbirth, including fluids to replace the blood that you have lost. You will also be given a dose of either the tranexamic acid or a placebo (a liquid which doesn’t contain tranexamic acid). This dose will be given as an injection into your vein. If after about 30 minutes you are still bleeding, or if the bleeding stops and starts again within 24 hours after the first dose, you may be given a second dose of the same. You will not receive more than two injections for the study. We do not know whether giving tranexamic acid on top of all the other treatments will help or not, so half the women in the study will receive tranexamic acid and the other half will receive a placebo. The choice of which treatment you receive is completely random and you will have an equal chance of receiving either one. Neither you nor the doctor treating you will know which treatment you receive. This information is kept on a confidential list at an independent location in London. The study involves no extra tests but your doctor/midwife will send brief details about your treatment and recovery to the Coordinating Centre in London. They will also send information about the health of your baby/ies. If after discharge from hospital and up to 42 days after treatment you develop any medical problems, please let the doctor named on this form know. This information will be used in strict confidence by the people working on the study and will not be released under any circumstances. 7) What are the possible risks of being in the study? Tranexamic acid is NOT a new drug and it is widely used to reduce bleeding in conditions such as major heart surgery. There is no conclusive evidence of serious side effects with short term use. But the study treatment may cause clots where they are not needed and, Page 33 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 Information sheet for woman and her representative, page 3 because the drug is not routinely used after childbirth, we do not know all the likely side effects. Your doctor will report to the trial organisers any unexpected problems you may have. 8) What are the possible benefits of being in the study? We hope that tranexamic acid may help reduce blood loss. The knowledge that we gain from this study will help women with postpartum haemorrhage worldwide in the future. 9) What information do we keep private? All information about you and the reason for bleeding after childbirth will be kept private. The only people allowed to look at the information will be the doctors who are running the study, the staff at the Coordinating Centre and the regulatory authorities who check that the study is being carried out correctly. The Trial Coordinating Centre may want to collect or copy some trial documents which will have your name and will include the signed Consent Form. This will help them to ensure that the trial is being carried out correctly. Your details will remain confidential and will be held in secure storage at the Trial Coordinating Centre. Your confidential information will be kept separately from the trial data and will be destroyed within five years of the trial ending. We will publish the results of the study in a medical journal so that other doctors can benefit from the knowledge, but your personal information will NOT be included and there will be no way that you can be identified. 10) Canyou change your mind about being in the study? You can always withdraw from the study at any time. You just need to say for example “I’ve decided | don’t want to be in this study now”. We hope that you will let us use information about how you got on, but if you do not want us to use it please tell the doctor. 11) Whatelse do you need to know? e In the event that something does go wrong and you are harmed during the study, the London School of Hygiene & Tropical Medicine who are organising the study would be responsible for claims for any non-negligent harm suffered as a result of participating in this study. e We will ask you to sign a separate consent form and give you a copy to keep and you can also keep this information sheet. e This study has been reviewed and approved by a Research Ethics Committee. 12) What happens afterwards? If after you leave this hospital you develop any problems at any time up to 42 days after you had your baby, we would definitely want to know about it. You will be given a card with the contact details of the research doctor at this hospital, which you should keep safely and show to anyone who may be treating you for any illness. If you would like to have a copy of the final results of this study, please let the research doctor know and s/he will ensure you receive a copy when it is published. Page 34 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009 APPENDIX 3d Informed Consent Form for woman ‘THE WOMAN TRIAL PATIENT CONSENT FORM. Principal Investigator name, Hospital name Hospital address Telephone contact number, email for PI CONSENT FORM FOR THE PATIENT THE WOMAN TRIAL An international randomised, double blind, placebo controlled trial Title of Research: Tranexamic acid for the treatment of postpartum haemorrhage: Hospital Code Number Name of Local Principal Investigator Patient Hospital ID Number} Randomisation Number BOK PACK Name of Patient Version Number: .0 / Version Date: 11 May 2009 1. | confirm that | have read and understood the opportunity to ask questions. affected. individuals to have access to these records. monitoring purposes only. in this trial. 6. lagree to take part in the above study, the WOMAN trial. information sheet Version Number. version date for the above study and have had the 2. understand that my participation is voluntary and that | am free to withdraw at any time, without giving any reason and without my medical care or legal rights being 3. | understand that sections of my medical notes and those of my baby/ies may be looked at by responsible individuals involved in the study. | give permission for these 4. | give permission for a copy of this consent form, which contains my personal information, to be made available to the Trial Coordinating Centre in London for 5. I give permission for my personal doctor to be given information about my participation PLEASE INITIAL BOXES given all the information about the trial and has verbally consented to taking part. Name of Patient Date Signature / Thumbprint or other mark (if unable to sign) Name of person taking consent Date Signature Name of local principal investigator Date Signature (Witness only if required) The patient is unable to sign and as a witness | confirm that the patient has been Name of witness Date Signature Original to be filed in the Investigator’s Study File, 1 copy for patient, 1 copy to be kept with woman's hospital records iT CONSENT FORM [MASTE Protocol Code: ISRCTN76912190 Page 35 of 36 Version 1.0 Protocol ISRCTN76912190 Version date: 11 May 2009