Woman Protocol

7/31/2019 Woman Protocol

1/40

Tranexamicacidforthetreatmentofpostpartum

haemorrhage:aninternationalrandomised,double

blindplacebocontrolledtrial

CLINICALTRIALPROTOCOLProtocolNumber:ISRCTN76912190

NUMBER DATE

FINALVERSION Version1.0 11May2009

AMENDMENT(ifany)


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Version1.0

FULLTITLEOF

SHORTTITLE:

TRIALACRONY

PROTOCOLNU

EUDRACTNU

BACKGROUND

Almostall(9

maternal m

postpartum

themwill

di

importantc

Systemicant

surgicalblo

identified 2

tranexamic

reduces tra

bleeding(RR

TXAsignifica

treatmentin

randomised

TXAinPPH

participants.

thequality

toosmallto

sideeffects.

statethatT

on which t

conducted.

AIM: TheW

hysterectom

woman wit

thromboem

OUTCOME:O

death(whic

PRIMARYOUT

causeofdea

SECONDARYO

(a) Death(b) Surgical

SUM

TUDY:

M:

MBER:

BER:

: Each year,

9%)ofthede

ortality acco

period. Abo

,with

an

av

useofmater

ifibrinolytica

d loss. Asys

11 randomis

cid (TXA) re

sfused volu

=0.67,95%CI

ntlyreduces

intractablep

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onductedby

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COME:Thepri

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Page1of36

olISRCTN76

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Page2of36

Version1.0 ProtocolISRCTN76912190 Versiondate:11May2009

laparotomy for other reasons, manual removal of placenta, intrauterine tamponade (packing or gauzing the

uterine cavity, condomcatheter, any other method of intrauterine tamponade), artery ligation, to achieve

haemostasis

(c) Bloodtransfusionbloodorbloodcomponentunitstransfused(d) HealthStatusmeasuredusingtheEQ5D(e)

Thromboembolic

events

(myocardial

infarction,

strokes,

pulmonary

embolism,

DVT)

(f) Otherrelevantmedicalevents(g) Lengthofstayathospital/timespentatanintensivecareunit(h) Needformechanicalventilation(i) Statusofbreastfedbaby/ies(j) CosteffectivenessTRIAL DESIGN: A large, pragmatic, randomised, double blind, placebo controlled trial among 15,000 women with aclinicaldiagnosisofpostpartumhaemorrhage

DIAGNOSISANDINCLUSION/EXCLUSIONCRITERIA:

Alllegallyadultwomenwithclinicallydiagnosedpostpartumhaemorrhagefollowingvaginaldeliveryofababyorcaesareansection.TheclinicaldiagnosisofPPHmaybebasedonanyofthefollowing:

estimatedbloodlossaftervaginaldeliveryofababy>500mLOR >1,000mLfromcaesareansectionOR bloodlosssufficienttocompromisethehaemodynamicstatusofthewoman

The fundamental eligibility criterion is the responsible clinicians uncertainty as to whether or not to use anantifibrinolytic agentinaparticularwomanwithpostpartumhaemorrhage.

Women for whom the responsible doctor considers there is a clear indication for antifibrinolytic therapyshouldnotberandomised.

Womenforwhomthereisconsideredtobeaclearcontraindication toantifibrinolytic therapyshouldnotberandomised.

Wheretheresponsibleclinicianissubstantiallyuncertainastotheappropriatenessofantifibrinolytic agentsinaparticularwomanwithPPH.

Therearenootherprespecifiedexclusioncriteria.TESTPRODUCT,REFERENCETHERAPY,DOSEANDMODEOF ADMINISTRATION:Adoseoftranexamicacid(1gramby intravenousinjection)orplacebo(sodiumchloride0.9%)willbegivenassoonaspossibleafterrandomisation. Ifafter30minutes

bleedingcontinues,orifitstopsandrestartswithin24hoursafterthefirstdose,aseconddosemaybegiven.

SETTING:ThistrialwillbecoordinatedfromtheLondonSchoolofHygiene&TropicalMedicine(UniversityofLondon)and conducted worldwide in hospitals in low, middle and high income countries. It is likely that most patient

recruitment

will

be

in

countries

with

high

rates

of

mortality

and

morbidity

from

postpartum

haemorrhage.

DURATIONOFTREATMENTANDPARTICIPATION:Thefirstdosewillbegivenimmediatelyafterrandomisation. Ifrequired,theseconddosewillbegivenupto24hoursafterthefirstdose.Nofurthertrialtreatmentwillbegiven.Participationwill

endatdischargefromrandomisinghospital,deathorat42dayspostrandomisationwhicheveroccursfirst.

CRITERIAFOREVALUATION:Allpatientsrandomlyassignedtooneofthetreatmentswillbeanalysedtogether,regardlessofwhetherornottheycompletedorreceivedthattreatment,onanintentiontotreatbasis.CLINICALPHASE: 3PLANNEDTRIALSTART: May2009PLANNEDDATEOFLASTPATIENTENROLMENT: 31December2014 PLANNEDDATEOFLASTOUTCOME 11February2015


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Version1.0

S

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ABLE

ummary

ableofcontent

INTROD

.1 Needf

.2 Tranex

.3 Potenti

.4 Objecti

TRIALD

.1 Overvie

.2 Settings

.3 Numbe

.4 Recruit

.5 Eligibilit

.6 Consen

.7

Rando

.8 Treatm

.8.1 Dosese

.8.2 Drugm

.8.3 Adminis

.8.4 Othert

.9 Advers

.10 Unblind

.11 Measur

.12 Dataco

.13 Monito

.14

End

of

t.15 Analysis

TRIALO.1 Sponso

.2 Indemn

.3 Protoco

.4 Indepe

.5 TrialSt

.6 Collabo

.7 TrialM

.8 Contact

.9 Publica

.10

Financi

ABBRE

REFERE APPENppendix1:En

ppendix2:O

ppendix3:Co

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Page3of36

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ect

11May2009

1

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Version1.0

Eachyear,w

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Page4of36

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Page5of36


1.1 NEEDFORATRIAL

TheWOMANTrialwillprovideareliablescientificbasisforrecommendationsastowhetherornottranexamicacid

shouldbeusedinthetreatmentofPPH.IfTXAreducesmortalityinwomenwithPPH,thiswouldbeofconsiderable

significance worldwide. There is a global commitment to the Millennium Development Goal (MDG) of reducing

maternal deaths by threequarters by the year 2015, a commitment that requires a reduction of the maternal

mortalityratioby5.5%eachyear.Becausematernalhaemorrhageaccountsforoveraquarterofdeaths,aneffective

treatmentforPPHwouldcontribute importantlytotheMDGofreducingmaternalmortality.TXAmightalsoreduce

theneedforhysterectomy,decreasetheriskofanaemiaandavoidtheneedforbloodtransfusion.Bloodisascarce

resource in many countries with a risk of transfusion transmitted infections. If TXA was effective in the hospital

setting,furtherresearchcouldbeconductedtoevaluate itsuse inthecommunity,possibly includingtheuseoforal

ratherthanintravenousadministration.

The results of this trial will be disseminated by publication in peer reviewed medical journals, conference

presentations,andinanupdatedversionoftheCochranesystematicreviewoftreatmentsforpostpartumbleeding.

Thereisevidencethathospitalsparticipatinginmulticentretrialsaremorelikelytoimplementthetrialresults.21

For

thisreason,alargeinternationalmulticentretrialliketheWOMANtrialcanbeexpectedtohaveasubstantialimpact

onclinicalpractice.Thelargenetworkofcollaboratingsiteswillensurethattheresultsaredisseminatedworldwide.

1.2 TRANEXAMICACIDANDITSEFFECTONBLEEDING

Inthehaemostaticprocess,coagulationoccursrapidlyatthesiteofadamagedvesselbuildingatightnetoffibrin,

while at the same time, the fibrinolytic system removes the fibrin deposits that could cause permanent vascular

occlusiononcevascularrepairhastakenplace.22

Thecoagulationandfibrinolyticsystemarebelievedtobeinastate

ofdynamicbalancewhichmaintainsanintactvascularsystem.Tranexamicacidisapotentantifibrinolytic agentthat

exerts its effect by blocking lysine binding sites on plasminogen molecules and has the potential to enhance the

effectivenessofthepatientsownhaemostaticmechanisms. Consequently,clotbreakdown(fibrinolysis) isinhibited

andexcessiveorrecurrentbleedingisreduced.

During delivery, when the placenta separates from the uterine wall, a sequence of physiologic and haemostatic

changesoccurthatreducebleeding:strongmyometrialcontractions,increasedplateletactivity,amassivereleaseof

coagulantfactorsandaparallelincreaseinthefibrinolyticactivity.23

Asaresult,thereisatheoreticalrationaleforthe

useofantifibrinolytic agentsinthetreatmentofpostpartumhaemorrhage.18,24,25

1.3 POTENTIALSIDEEFFECTSOFTRANEXAMICACID

As TXA inhibits the breakdown of fibrin deposits already formed, it might theoretically increase the risk of

thromboembolism. However,thesystematicreviewofTXAinsurgerydidnotshowstatisticallysignificantincreasesin

therisksofanyofthethromboemboliceventsassessed.14


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Page6of36


Events EffectofTXARR 95%CI

MyocardialInfarction 0.96 0.481.90

Stroke 1.25 0.473.31

Deepvenousthrombosis 0.77 0.371.61

Renalfailure 0.73 0.163.32

Duringpregnancy,womenhavean increasedriskof thromboembolic events,comparedwithnonpregnantwomen.

Theabsoluteriskofsymptomaticvenousthrombosisduringpregnancyhasbeenestimatedtobebetween0.5and3.0

per 1,000 women based on studies using radiographic documentation.2628

Studies using objective criteria for

diagnosis have found that antepartum deep vein thrombosis (DVT) is as common as postpartum thrombosis and

occurswithequalfrequencyinallthreetrimesters.26

Apopulationbasedcohortstudyestimatedan incidenceofthromboembolic eventstobe200per100,000woman

years.29

DVTwasthreetimesmorecommonthanpulmonaryembolismandthromboembolic eventswerefivetimes

more likely in the postpartum period than during the pregnancy. This was particularly evident with pulmonary

embolism which was 15 times more likely to occur in the postpartum period than during the pregnancy.

Thromboembolic eventswillbecollectedroutinelyaspartofthedatacollectionprocessforthistrial.

TXA passes into breast milk in very low concentrations, approximately one hundredth of the concentration in the

maternal blood. An antifibrinolytic effect in the infant is very unlikely at this low concentration.30

The

thromboembolic effectsonbreastfedbabieswillbeassessedinthistrial.

TXAisnotanewdrugandisgenerallywelltolerated.Adverseeventsareuncommonandusuallymanifestasnausea

ordiarrhoea,oroccasionallyasorthostaticreactions.18

1.4 OBJECTIVE

The WOMAN trial will provide reliable evidence as to whether the antifibrinolytic agent tranexamic acid reduces

mortality, hysterectomy and other morbidities in woman with clinically diagnosed postpartum haemorrhage.

Thromboembolic effectsonbreastfedbabieswillbeassessed.


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Version1.0

2

2.1 OVE

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Page7of36

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lberandomis

indouthow

uncertainty

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hatparticula

errepresent

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ldallowthep

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10/40

Page8of36


UnitedKingdomto2%inNigeriaor14%inCongoBrazzaville.Basedontheseranges,abaselineeventrateof2.5%for

mortalityand2.5%forhysterectomymightreasonablybeexpected.

Samplesizeandsizeoftreatmenteffectthatshouldbedetectable:Assumingacontrolgroupeventrateof2.5%formortalityand2.5%forhysterectomywith1%ofwomenhavingbotha

hysterectomy and then dying, a study with 15,000 women would have over 90% power (two sided alpha=5%) to

detectaclinically important25%reductionfrom4%to3% intheprimaryendpointofmortalityorhysterectomy.A

surveyofbaselineeventratesamonghospitalsthathaveexpressedinterestintakingpartshowsthatbaselineevent

ratesofthismagnitudearerealisticandthathigherbaselineeventratesmightreasonablybeexpected.Experience

from theCRASH1andCRASH2clinical trialssuggests that theanticipatedratesof loss to followup (less than1%)

wouldnotimpactimportantlyonstudypower.

2.4 RECRUITMENTOFCOLLABORATINGINVESTIGATORS

The trial will recruit collaborating sites from all countries worldwide and will continue to add sites to ensure the

samplesizeisachieved.Suitablecollaboratingsitesandinvestigatorswillbeassessedonthelevelofobstetricservice

theyprovideandtheirabilitytoconductthetrial. InadvanceofthetrialstartingatasitethePrincipalInvestigator

mustagreetoadheretoGoodClinicalPracticeGuidelinesandallrelevantregulationsintheircountry.Inaddition,all

relevantregulatoryandethicsapprovalswillneedtobeinplace.

2.5 ELIGIBILITY

Immediatelyafterdeliveryofthebaby/ies,allusualcareshouldbegivenforthepreventionofPPH.Somebleedingis

expectedafterdelivery. However,ifbleedingcontinuesandadiagnosisofPPHismade,allusualtreatmentsshould

begivenandatthesametimetheassessmentfor inclusion inthetrialshouldbemade. It is importanttoconsider

inclusionasearlyaspossible.

Inclusioncriteria:Alllegallyadultwomenwithclinicallydiagnosedpostpartumhaemorrhagefollowingvaginaldeliveryofababyor

caesareansection;womenmayhavedeliveredtheirbabiesataparticipatinghospitaloroutsideaparticipating

hospital,withhospitaladmissionfollowingdelivery:

wheretheresponsibleclinicianissubstantiallyuncertainastowhetherornottouseTXA whenconsenthasbeengivenaccordingtoapprovedprocedures

TheclinicaldiagnosisofPPHmaybebasedonanyofthefollowing:

estimated

blood

loss

after

vaginal

delivery

of

a

baby

>

500

mL

OR

>1000mLfromcaesareansectionOR estimatedbloodlossenoughtocompromisethehaemodynamicstatusofthewoman

Exclusioncriteria:

Women for whom the responsible clinician considers there is a clear indication for TXA should not berandomised.

Womenforwhomtheresponsibleclinicianconsidersthereisaclearcontraindication forTXAshouldnotberandomised(e.g.aknownthromboembolic eventduringpregnancy).

The

fundamental

eligibility

criterion

is

the

responsible

clinicians

uncertainty

as

to

whether

or

not

to

use

an

antifibrinolytic agentinaparticularwomanwithpostpartumhaemorrhage.


11/40

Version1.0

The TXA su

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Page9of36

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12/40

Page10of36


pregnant women (Appendix 3a). Refusal to be considered for participation will be documented in the womans

medicalrecordsandherdecisionrespected.

Followingdeliveryofherbaby,andonceawomanhasbeendiagnosedwithPPH,acriticalclinicalemergencysituation

exists.Theriskofdeath ishighestearlyafterdelivery.Theprocessbywhich informationwillbegivenandconsent

obtainedwilldependontheneedforurgentclinicalinterventionandherphysical,mentalandemotionalstate.Also,

theavailabilityandabilityofapersonalrepresentativetomakeadecisiononthewomansbehalfwillhavetobetaken

intoconsideration. Theapproachwhichwillallowthewomantohavethemostinputintothedecisionmakingprocess

withoutendangeringherlifewillbeutilised:

a) The woman is fully competent: The woman will be approached with the agreement of the primary carer (themidwife 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(Appendix3d).Ifthewomanisunabletoreadorwrite,thentheinformationsheetmaybereadtoherand

shemaythenmarktheconsentformwitheitheracrossorthumbprint. Inthisevent,awitnessNOTassociatedwith

thetrial,mustprovideafullsignatureconfirmingthemark.

b) The womans mental capacity is impaired and either a Personal or Professional representative is available:Informationshouldbegiventothewomantakingherlevelofmentalimpairmentintoconsideration. Oralrefusalby

thewomanshouldberespectedandsheshouldnotbeenrolled.

a. IfaPersonalRepresentative(PeR)who isknowledgeableaboutthewomansvaluesandbeliefs isavailable,anInformationSheetwillbeprovided.Opportunityforquestionsshouldbegivenandwrittenconsentobtained.If

thePeRisunabletoreadorwrite,thentheinformationsheetmaybereadtohim/herandamarkwitheithera

cross or thumbprint made on the consent form. In this event, a witness NOT associated with the trial, must

provideafullsignatureconfirmingthemark.

b. IfaPersonalRepresentativeisnotavailableandthewomanisunabletoprovidevalidinformedconsent,thenanindependentdoctor/midwife/othersitestaffallowedtofulfilthisrole(ideallytheprimarycarerifs/heisnot

partofthetrialteam)maybeaskedtoconsentasaProfessionalRepresentative(PrR). Informedconsentgiven

byarepresentative shallrepresentthewomanspresumedwill.

c)ThewomansmentalcapacityisimpairedandneitheraPersonalnorProfessionalrepresentativeisavailable:Insituations where the woman is facing a clinical emergency and no PeR/PrR is available, the investigator and ONE

independentperson(doctorormidwife)who isnotparticipating inthistrialmayenrolthewoman intothetrialby

certifyinginwritinginthewomansmedicalrecordsthat:

the

woman

is

facing

a

life

threatening

postpartum

haemorrhage;

thewomanisunabletogiveherconsentasaresultofhermedicalcondition; itisnotfeasibletocontactthewomansPeR/PrRtoobtainconsentwithinthewindowperiod;and neitherthewomannorthewomansPeR/PrRnoranymemberofthefamilyhasinformedtheinvestigatorof

anyobjectionstothewomanbeingusedasaparticipantinthistrial.

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

overviewoftheconsentprocedureisprovidedinAppendix3b.

Therequirementsoftherelevantethicscommitteewillbeadheredtoatalltimes.


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Page11of36


2.7 RANDOMISATION

Randomisationcodeswillbegeneratedandsecuredbyan independentstatisticalconsultant fromSealedEnvelope

Ltd(UK).ThecodeswillbemadeavailabletoBreconPharmaceuticalsLimited(UK)explicitlyforthetreatmentpacksto

becreatedinaccordancewiththerandomisationlist.Eligibilitywillbedeterminedfromtheroutinelycollectedclinical

information and no trialspecific tests are required. Women eligible for inclusion should be randomised to receive

eitheractive(tranexamicacid)orplacebo(sodiumchloride0.9%)treatmentandthetrialtreatmentstartedassoonas

possible.

Baselineinformationwillbecollectedonthetrialentryformandthenextlowestconsecutivelynumberedpackwillbe

takenfromaboxofeighttreatmentpacks.Whenthetreatmentampouleisconfirmedasbeingintact,atthispointthe

patientisconsideredtoberandomisedontothetrial.TheentryformdatawillbesenttotheTrialCoordinatingCentre

assoonaspossible.Onceapatienthasbeenrandomised,theoutcomeofthewomanshouldbeobtainedevenifthe

trialtreatmentisinterruptedorisnotactuallygiven.

2.8 TREATMENT

Tranexamicacidwillbecomparedwithmatchingplacebo(sodiumchloride0.9%).2.8.1 DOSESELECTION

In randomised trials of antifibrinolytic agents in surgery, TXA dose regimens vary widely. Loading doses range

from2.5mg/kgto100mg/kgandmaintenancedosesfrom0.25mg/kg/hourto4mg/kg/hourgivenoverperiods

of one to twelve hours. Studies examining the impact of different doses of tranexamic acid on bleeding and

transfusion requirements showed no significant differences between a high dose and a low dose. Studies in

cardiacsurgeryhaveshownthata10mg/kginitialdoseofTXAfollowedbyaninfusionof1mg/kg/hourproduces

plasmaconcentrationssufficienttoinhibitfibrinolysisinvitro.Horrowetal(1995)examinedthedoseresponse

relationship of TXA and concluded that 10 mg/kg followed by 1 mg/kg/hour decreases bleeding in cardiac

surgery,but largerdosesdidnotprovideanyadditionalhaemostaticbenefit.32

TrialsoftheuseofTXAforthe

preventionofobstetrichaemorrhageusedTXAatadoseof1gramwithoutmajorcomplications.20

Intheemergencysituation,theadministrationofa fixeddose ismorepracticablesinceweighingwomenwith

PPHwouldbedifficult.Therefore,afixeddoseof1gramofTXAinitiallyfollowedby1gramifbleedingcontinues,

whichiswithinthedoserangewhichhasbeenshowntoinhibitfibrinolysisandprovidehaemostaticbenefit,has

beenselectedfortheWOMANtrial.Onthebasisofexperienceinsurgery,thedoseselectedwouldbeefficacious

for

larger

patients

(>100

kg)

but

also

safe

in

smaller

patients

(


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Page12of36


Placebo (sodium chloride 0.9%) will be manufactured specially to match the tranexamic acid by South Devon

Healthcare NHS Trust, Kemmings Close, Paignton, Devon, TQ4 7TW, under UK Manufacturers authorisation

Number:MS13079/MA(IMP)13079.

Ampoulesandpackagingwill be identical inappearance. The blindingprocess and firststage Qualified Person

(QP)releasewillbedonebyBreconPharmaceuticalsLimited,WyeValleyBusinessPark,HayonWye,Hereford

HR35PG,underUKManufacturersauthorisationNumberMIA11724/MIAIMP11724.Theblindingprocesswill

involve complete removal of the original manufacturers label and replacement with the clinical trial label

bearing therandomisationnumber whichwillbe usedas thepack identification. Other pack label textwill be

identicalforbothTXAandplacebotreatmentsandwillbe incompliancewithrequirements for investigational

medicinalproducts.TreatmentpackscontainingTXAandplacebowillbepackedinbalancedblocksof8(4TXA:

4Placebo)intoaboxinrandomorder.

BreconPharmaceuticalsLimitedwillalsoberesponsibleformaintainingtheProductSpecificationFile(PSF)until

final database lock and unblinding of the trial data. Quality control checks to assure blinding process will be

performed on a random sample of final QP released drug packs. High Performance Liquid Chromatography

analyses(HPLC)separationofknowntranexamicacidwillbeassessedagainstblindedsamplestoconfirmwhich

ampoulecontainstheplaceboandactivetreatments.Thetestedsampleswillbeunblindedtoassureaccuracyof

blinding.

TheTrialsCoordinatingCentre (TCC)willberesponsible forassuringallrelevantapprovalsareavailableatthe

TCCbeforereleaseofthetrialtreatmenttoasite.

2.8.3 ADMINISTRATIONOFTRIALTREATMENT

Eachtreatmentpackwillcontain:

4x500mgampoulesoftranexamicacidorplacebo 2xsterile10mLsyringeand21FGneedle Stickers(forattachingtodataformsandpatientmedicalrecords)

TREATMENT AMPOULES DOSE(TRANEXAMICACIDORPLACEBO) ADMINISTRATIONINSTRUCTION

DOSE1 2 1gram

To be administered by intravenous injection at an

approximate rate of 1mL/minute to all randomised

womenassoonaspossibleafterrandomisation.

DOSE2 2 1gram

If

after

30

minutes

bleeding

continues,

or

if

it

stops

and

restarts within the 24 hours after the first dose, a second

dose may be given. To be administered by intravenous

injectionatanapproximaterateof1mL/minute.

Thetrialtreatmentinjectionsshouldnotbemixedwithbloodfortransfusion,orinfusionsolutionscontaining

penicillinormannitol.

2.8.4 OTHERTREATMENTSFORPPH

There is awide spectrum of first and second line treatments of postpartum haemorrhage.As the trial will be

conducted

worldwide,

each

participating

site

should

follow

its

own

clinical

guidelines

for

the

treatment

of

postpartum haemorrhage. Information on other treatments given will be collected on the outcome form.


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Page13of36


Tranexamic acid or placebo would be an additional treatment to the routine management of postpartum

haemorrhage.

2.9 ADVERSEEVENTS(AEs)

TXA has a well documented safety profile. No increase in thromboembolic risks associated with its use has been

shown todate.However,asdiscussed inSection1.3anexpectedcomplicationofpregnancy isan increasedriskof

thromboembolic events.Thistrialwillcollectdataonallthromboemboliceventsassecondaryoutcomes,andallsuch

eventsareroutinelyreportedtotheindependentdatamonitoringcommittee(DMC)forunblindedreview.Definitions:Adverseevent(AE)Anyuntowardmedicaloccurrenceaffectingatrialparticipantduringthecourseofaclinicaltrial

SeriousAdverseEvent(SAE)Aseriousadverseevent(experience)isanyuntowardmedicaloccurrencethatatanydose

resultsindeath; islifethreatening; requiresinpatienthospitalisation orprolongationofexistinghospitalisation; resultsinpersistentorsignificantdisability/incapacity; or isacongenitalanomaly/birthdefect.AdverseReaction(AR)Anadverseeventwhenthereisatleastapossibilitythatitiscausallylinkedtoatrialdrugorintervention

SeriousAdverseReaction(SAR)SAEthatisthoughttobecausallylinkedtoatrialdrugorintervention

SuspectedUnexpectedSeriousAdverseReaction(SUSAR)AnunexpectedoccurrenceofaSAR;thereneedonlybeanindexofsuspicionthattheeventisapreviouslyunreported

reactiontoatrialdrugorapreviouslyreportedbutexaggeratedorunexpectedlyfrequentadversedrugreaction.

ReportingofAdverseEventsforthistrial:Death,lifethreateningcomplicationsandprolongedhospitalstayareprespecifiedoutcomestobereported inthistrialandalsotothe independentdatamonitoringcommittee.Thisclinical

trialisbeingconductedinacriticalemergencycondition,usingadrugincommonuse.Itisimportanttoconsiderthe

naturalhistoryofthecriticalmedicaleventaffectingeachwomanenrolled,theexpectedcomplicationsofthisevent

andtherelevanceofthecomplicationstoTXA.

Adverseeventstobereportedusinganadverseeventreportingformwillbe limitedtothoseNOTalready listedas

primaryorsecondaryoutcomes,yet,whichmightreasonablyoccurasaconsequenceofthetrialdrug.Eventsthatare

partofthenaturalhistoryoftheprimaryeventofPPHorexpectedcomplicationsofPPHshouldnotbereportedas

adverseevents.

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

irrespectiveofthecause.


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Page14of36


IfaSeriousAdverseEventoccurs,thisshouldbe loggedbycallingtheTrialCoordinatingCentreEmergencyHelpline

and a written report submitted within 24 hours. The TCC will coordinate the reporting of all SAEs to all relevant

RegulatoryAgencies,EthicsCommitteesandlocalinvestigatorsasperlocallegalrequirements.

2.10 UNBLINDING

Ingeneral thereshouldbenoneed tounblind theallocated treatment. Ifsomecontraindication toantifibrinolytic

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 orplacebo. Inthosefewcaseswhenurgentunblindingisconsiderednecessary,a24hourtelephone

servicewillbeavailableanddetailsprovided inthe InvestigatorsStudyFileandwallposters.Thecallerwillbetold

whether the patient received antifibrinolytic or placebo. An unblinding report form should be completed by the

investigator.2.11 MEASURESOFOUTCOME

Afterapatienthasbeenrandomised,outcomeinhospitalwillbecollectedevenifthetrialtreatmentisinterruptedor

isnotactuallygiven.NoextratestsarerequiredbutashortsinglepageOutcomeFormwillbecompleted6weeks(42

days)afterrandomisation, atdischargefromtherandomisinghospitaloratdeath(whicheveroccursfirst).

PrimaryOutcome:Theprimaryoutcomeistheproportionofwomenwhodieorundergohysterectomy.Theprimarycauseofdeathwillbedescribed.Secondaryoutcomes:(a) Death(b) Surgical Interventions including hysterectomy; brace suture (BLynch/Cho); selective arterial embolisation;

laparotomy for other reasons; manual removal of placenta; intrauterine tamponade (packing or gauzing the

uterine cavity, condomcatheter, any other method of intrauterine tamponade); artery ligation, to achieve

haemostasis.

(c) Bloodtransfusionbloodorbloodcomponentunitstransfused(d) HealthRelatedQualityoflife(HRQoL)willbemeasuredbytheproxyversionoftheEQ5Datdischargefromthe

randomisinghospitalor inhospitalat42daysafterrandomisation. TheEQ5D includessingle itemmeasuresofmobility, selfcare, usual activities, pain/discomfort and anxiety/depression. Each item is coded using 3 levels

(1=noproblems;2=someproblems;3=severeproblems).The instrument includesaglobalratingofcurrent

healthusing

avisual

analogue

scale

(VAS)

ranging

from

0(worst

imaginable)

to

100

(best

imaginable).

The

EQ

5D

isa genericmeasureofhealthstatusthatprovidesasimpledescriptiveprofileandasingleindexvaluethatcan

beusedintheclinicalandeconomicevaluationofhealthcare.

(e) Thromboembolic events(myocardialinfarction,strokes,pulmonaryembolism,deepveinthrombosis)(f) Medicaleventsincludingrenalfailure,AdultRespiratoryDistressSyndrome,hypertensivedisordersofpregnancy

(includingHELLPSyndrome,eclampsia,toxaemiaofpregnancy)andotheradverseeventsreported

(g) Lengthofstayathospital/timespentatanintensivecareunit(h) Receiptofmechanicalventilation(i) Status of baby/ies: The health status of the baby/ies will be ascertained and information collected on any

thromboembolicevents

in

breastfed

babies


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Page15of36


(j) Costeffectiveness analysis: An economic analysis will be relevant if TXA clearly demonstrates efficacy inachieving itsclinicalaims. Inthiscase,thestudywillbeundertaken intheformofacosteffectivenessanalysis

withtheaimofestimatingtheincrementalcosteffectivenessratiocomparingtheuseofTXAwithnormalclinical

practice.Analysiswillbebasedonadjustedlifeyearsgained.AfurtheranalysiswillexploretheuseoftheEQ5D

datatoqualityadjustsurvival. Inthisstudy,theeconomicanalysis isclearlyboundedasvirtuallyallsignificant

resourceusewilloccurintheinitialperiodofhospitalisation. Assuch,neitheralongtermresourceanalysisnor

ananalysisofoutofhospitalcostswillberequired.ThetrialuseofTXAislikelytomirroritsuseinnormalclinical

practice, hence the costeffectiveness estimated in the trial (adjusted for protocol driven costs) will closely

approximatecosteffectivenessinactualclinicalpractice.Dataonphysicalresourceconsumption(e.g.lengthand

nature of hospital stay) will be collected for each patient and a common unit cost at a country level will be

applied.Asensitivityanalysiswillbeundertakentoassesstherobustnessoftheeconomicanalysisinresponseto

variations in key variables such as drug prices. In all cases, the economic analysis will be integrated with the

clinicaltrialprocedurestooptimiseefficiencyandminimiseinconveniencetopatients.

2.12 DATACOLLECTION

ThistrialwillbecoordinatedfromLSHTMandconductedinhospitalsinlow,middleandhighincomecountries.Most

recruitmentwillbeincountrieswithhighratesofmortalityandmorbidityfrompostpartumhaemorrhage.Datawill

becollectedateachsitebylocalinvestigatorsandtransmittedtotheTCC.Onlydataoutlinedontheentry,outcome

andadverseeventformswillbecollectedforthistrial.

Relevantdataonanentryformwillbecollectedbeforerandomisationtoassesseligibilityandtheformcompletedif

randomised. Theoutcomeformshouldbecompletedatdeath,dischargefromtherandomisinghospitalor6weeks

(42 days) after randomisation whichever occurs first. This data should be collected from the womans and her

baby/iesroutinemedicalrecordsasnospecialtestsarerequired.

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

handledasfollows:

Datacollectedtothepointofwithdrawalofconsentwillbeusedaspartoftheintentiontotreatanalysis Allrelevantadverseeventsidentifiedwillbereportedasrequiredtoallrelevantauthorities

Toallowforvariationinavailabletechnologyfordatatransferavarietyofmethodswillbeusedinthistrial.Datawill

becollectedbytheinvestigator onpapercasereportforms(CRFs)andtransmittedtotheTCCeitherasapaperform

(byfaxoremail)orbyenteringthedatadirectly intothetrialdatabase.Datacanalsobetransmittedbyentryonto

electronic

data

files

which

can

be

emailed

or

uploaded

to

the

TCC

secure

web

server.

In

cases

where

electronic

data

filesareused,datastoredonthe investigators computer(s)anddataduringtransferwillbesecuredbyencryption.

Thedatawillbeusedinaccordancewithlocallawandethicscommitteeapproval.

2.13 MONITORING

GCPsection5.18.3statesinregardtomonitoring,Thedeterminationoftheextentandnatureofmonitoringshould

bebasedonconsiderationssuchastheobjective,purpose,design,complexity,blinding,sizeandendpointsofthetrial.

In general there is a need for onsite monitoring, before, during, and after the trial; however in exceptional

circumstancesthesponsormaydeterminethatcentralmonitoringinconjunctionwithproceduressuchasinvestigators

trainingand

meetings,

and

extensive

written

guidance

can

assure

appropriate

conduct

of

the

trial

in

accordance

with

GCP.Statisticallycontrolledsamplingmaybeanacceptablemethodforselectingthedatatobeverified.


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Page16of36


Thistrialisalarge,pragmatic,randomisedplacebocontrolledtrial.Theintervention(tranexamicacid)hasmarketing

authorisationinmanycountriesandhasbeeninclinicaluseforover40years.Itssafetyprofileiswellestablishedand

nosignificantseriousadverseeventsassociatedwithitsusehavebeenidentified.Thetrialwillroutinelycollectdata

onadverseeventswhichmaytheoreticallybeassociatedwiththisproductandtheconditionunderinvestigation, and

these will be reviewed routinely by the independent Data Monitoring Committee (DMC). Other than consent, the

administration ofthetrialdrugusingaroutineclinicalprocedureandcollectingroutineclinicalinformationfromthe

medicalrecords, therearenocomplexproceduresor interventions fortheparticipantsor investigators inthis trial.

Clinicalmanagementforunderlyingconditionswillremainaspereachhospitalsstandardprotocol.Basedonthese

factors, the probability of harm or injury (physical, psychological, social or economic) occurring as a result of

participationinthisresearchstudyhasbeenassessedaslowrisktoparticipantsineachofthesecategories.Basedon

thelowrisksassociatedwiththistrial,aMonitoringPlantoassureappropriateconductofthetrialwillbedeveloped

which will incorporate 100% central monitoring in conjunction with procedures such as investigator training and

meetingsandwrittenguidance.Inaddition,alldatawillbesubjecttostatisticalmonitoringandat least10%ofdata

willbesubjectedtoonsitemonitoring.

Investigators/institutionsarerequiredtoprovidedirectaccesstosourcedata/documentsfortrialrelatedmonitoring,

audits,ethics

committee

review

and

regulatory

inspection.

All

trial

related

and

source

documents

must

be

kept

for

fiveyearsaftertheendofthetrial.

2.14 ENDOFTRIALFORPARTICIPANTS

The trial ends either at death, discharge, or six weeks postrandomisation, whichever occurs first. If during the

treatmentphaseawomandevelopsanadverseeventthetrialdrugshouldbestopped,woman treated in linewith

localproceduresandthenfollowedup.

ThetrialmaybeterminatedearlybytheTrialSteeringCommittee(TSC).TheDMCmaygiveadvice/recommendation

forthe

early

termination

of

the

trial

but

the

TSC

is

responsible

for

the

final

decision.

2.15 ANALYSIS

Themainanalyseswill compare all thoseallocated antifibrinolytic treatmentversus thoseallocatedplacebo,onan

intention to treat basis, irrespective of whether they received the allocated treatment or not. Results will be

presentedasappropriateeffectestimateswithameasureofprecision(95%confidenceintervals).Subgroupanalyses

for the primary outcome will be based on type of delivery (vaginal or caesarean section); administration or not of

prophylacticuterotonics;andonwhethertheclinicaldecisiontoconsidertrialentrywasbasedprimarilyonestimated

bloodlossaloneoronhaemodynamic instability.Interactiontestwillbeusedtotestwhethertheeffectoftreatment

(ifany)

differs

across

these

subgroups.

Between

sites

heterogeneity

in

effectiveness

will

be

explored.

All

analyses

will

be conducted in STATA. A detailed Statistical Analysis Plan setting out full details of the proposed analyses will be

finalisedbeforethetrialdatabaseislockedforfinalanalysis.


19/40

Version1.0

3

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Page18of36


3.4 INDEPENDENTDATAMONITORINGCOMMITTEE(DMC)

Membership:NAME AFFILIATION EXPERTISEProfessor

Sir

Iain

Chalmers

James

Lind

Initiative,

Oxford,

UK

Largescalerandomisedcontrolledtrials;

Obstetriccare

ProfessorPisakeLumbiganon

ProfessorofObstetrics&Gynaecology;

Convenor,ThaiCochraneNetwork;

FacultyofMedicine,KhonKaen

University,Thailand

Obstetriccare

DrGildaPiaggio StatistikaConsultoria,SoPaulo,Brazil

Statistician(Extensiveexperienceof

reproductivehealthandresearchatthe

WorldHealthOrganization)

Mortalityand

severe

morbidity

is

expected

within

the

target

population.

To

provide

protection

for

study

participants,

an independentDMChasbeenappointed for thistrial tooversee thesafetymonitoring.TheDMCwillreviewona

regular basis accumulating data from the ongoing trial and advise the Trial Steering Committee regarding the

continuingsafetyofcurrentparticipantsandthoseyettoberecruited,aswellasreviewingthevalidityandscientific

meritofthetrial.

TheDMCcomposition,name,titleandaddressofthechairmanandofeachmember,willbegivenintheDMCCharter

which will be in line with that proposed by the DAMOCLES Study Group.33

Membership includes expertise in the

relevantfieldofstudy,statisticsandresearchstudydesign.TheDMCCharterincludes,butisnotlimitedto,defining:

(a) thescheduleandformatoftheDMCmeetings(b) theformatforpresentationofdata(c) themethodandtimingofprovidinginterimreports(d) stoppingrules

StandardOperatingProcedures:TheDataMonitoringCommittee(DMC)hastheresponsibility fordecidingwhether,whilerandomisationisinprogress,theunblindedresults(ortheunblindedresultsforaparticularsubgroup),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

definitelyfavourableforall,orforaparticularcategoryof,participantsintermsofthemajoroutcome;(2)Theresults,

ifrevealed,wouldbeexpectedtosubstantiallychangetheprescribingpatternsofclinicianswhoarealreadyfamiliar

with

any

other

trial

results

that

exist.

Exact

criteria

for

proof

beyond

reasonable

doubt

are

not,

and

cannot

be,

specifiedbyapurelymathematicalstoppingrule,but theyarestrongly influencedbysuchrules.DMCCharter is in

agreementwiththePetoHaybittle34,35

stoppingrulewherebyan interimanalysisofmajorendpointwouldgenerally

need to involve a difference between treatment and control of at least three standard errors tojustify premature

disclosure.An interimsubgroupanalysiswould,ofcourse,have tobeevenmoreextremetojustifydisclosure.This

rulehastheadvantagethattheexactnumberandtimingofinterimanalysesneednotbeprespecified.Insummary,

thestoppingrulesrequireextremedifferencestojustifyprematuredisclosureandinvolveanappropriatecombination

ofmathematicalstoppingrulesandscientificjudgment.


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Page19of36


3.5 TRIALSTEERINGCOMMITTEEMembership:NAME AFFILIATION EXPERTISEProfessorAdrianGrant

(Chair)

Director,HealthServicesResearchUnit,

UniversityofAberdeen

HealthServicesResearch;Randomised

ControlTrials

ProfessorIanRoberts

(PrincipalInvestigator)

LondonSchoolofHygiene&Tropical

Medicine

Epidemiology;RandomisedControlTrials;

Conductoflargescaleinternationaltrials

DrMetinGlmezogluDrMetinGlmezoglu

WorldHealthOrganization,Geneva

Obstetrician; CoordinatingEditorofthe

WHOReproductiveHealthLibrary;

RandomisedControlTrials

DrKaosarAfsana BRACHealthProgramme,Bangladesh

Reproductive&SexualHealth&Rights;

RuralandUrbanMaternal,Neonataland

ChildHealthProgrammeinBRAC

DrOladapoOlayemiUniversityCollegeHospital,Ibadan,

Nigeria

ConsultantObstetrician;perspectiveon

obstetricsinadevelopingcountry

Professor

Beverley

Hunt

Kings

College,

London

ProfessorofThrombosis&Haemostasis,

RandomisedControl

Trials

TheroleoftheTrialSteeringCommittee(TSC)istoprovideoverallsupervisionofthetrial. Inparticular,theTSCwill

concentrate on the progress of the trial, adherence to the protocol, patient safety and consideration of new

information. TheTSCmustbeinagreementwiththefinalProtocoland,throughoutthetrial,willtakeresponsibility

for:

(a) majordecisionssuchasaneedtochangetheprotocolforanyreason(b) monitoringandsupervisingtheprogressofthetrial(c) reviewingrelevantinformationfromothersources(d) consideringrecommendationsfromtheDMC(e) informingandadvisingtheTrialManagementGrouponallaspectsofthetrial

Thesteeringcommitteeconsistsofexperiencedobstetricexperts,clinicaltrialistsaswellasaReproductive&Sexual

Health&Rightsrepresentative.Facetofacemeetingswillbeheldatregularintervalsdeterminedbyneed,butnoless

thanonceayear.ATSCCharterwillbeagreedatthefirstmeetingwhichwilldetailhowitwillconductitsbusiness.

Whenoutcomedataareavailablefor1,000trialparticipants,theTSCwillreviewtherateofrecruitmentintothetrial

and the overall event rates. The TSC willconsider the extent to which the rateof recruitment and the event rates

correspondtothoseanticipatedbeforethetrialandwilltakewhateveractionisneededinlightofthisinformation.

3.6 COLLABORATORSRESPONSIBILITIES

CoordinationwithineachparticipatinghospitalwillbethroughalocalPrincipalInvestigatorwhoseresponsibilitywill

bedetailedinanagreementinadvanceofstartingthetrialandwillinclude:

Ensureallnecessaryapprovalsareinplacepriortostartingthetrial Delegatetrialrelatedresponsibilities onlytosuitablytrainedandqualifiedpersonnel Trainrelevantmedicalandnursingstaffwhoseeobstetricpatientsandensure that theyremainawareof the

stateofthecurrentknowledge,thetrialanditsprocedures(therearewallcharts,pocketsummariesandasetof

slidestoassistwiththis)

Agree

to

comply

with

the

final

trial

protocol

and

any

relevant

amendments

Ensurethatallwomenwithpostpartumhaemorrhageareconsideredpromptlyforthetrial


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Page20of36


Ensureconsentisobtainedinlinewithlocalapprovedprocedures EnsurethatthepatiententryandoutcomedataarecompletedandtransmittedtotheTCCinatimelymanner EnsuretheInvestigatorsStudyFileisuptodateandcomplete EnsureallAdverseEventsarereportedpromptlytotheTCC Accountabilityfortrialtreatmentsattheirsite EnsurethetrialisconductedinaccordancewithICHGCPandfulfilsallnationalandlocalregulatoryrequirements Allowaccesstosourcedataformonitoring,auditandinspection Beresponsibleforarchivingalloriginaltrialdocuments includingthedataformsforfiveyearsaftertheendof

thetrial3.7 TRIAL MANAGEMENT GROUP (TMG) AND TRIAL COORDINATING CENTRE (TCC)

RESPONSIBILITIES

TheTrialManagementGroupwillconsistoftheProtocolCommitteemembers(Section3.3)plusatrialmanager,datamanagerandtrialadministrator.

The

TCC

will

act

on

behalf

of

the

Sponsor

and

will

be

responsible

to

the

TMG

to

ensure

that

all

Sponsors

responsibilities arecarriedout.Theresponsibilities willinclude(butnotlimitedto):

o ReporttotheTrialSteeringCommitteeo MaintaintheTrialMasterFileo Identifytrialsiteso Confirmallapprovalsareinplacebeforereleaseofthetrialtreatmentandthestartofthetrialatasiteo Providetrainingaboutthetrialo Providestudymaterialso Datamanagementcentreo 24houradviceandunblindingserviceo Givecollaboratorsregularinformationabouttheprogressofthestudyo Respondtoanyquestions(e.g.fromcollaborators)aboutthetrialo Ensuredatasecurityandqualityandobservedataprotectionlawso Safetyreportingo EnsuretrialisconductedinaccordancewiththeICHGCPo Statisticalanalysiso Publicationoftrialresults

3.8 CONTACTINGTHETCCINANEMERGENCY

Forurgent

enquiries,

adverse

event

reporting

and

unblinding

queries

investigators

can

contact

the

24

hour

telephone

serviceprovidedbytheTCC.AcentraltelephonenumberisgivenintheInvestigatorsStudyFileandposters.

3.9 PUBLICATIONANDDISSEMINATIONOFRESULTS

AlleffortswillbemadetoensurethatthetrialprotocolandresultsarisingfromtheWOMANtrialarepublishedinan

establishedpeerreviewedjournal.Atleastonepublicationofthemaintrialresultswillbemade.Allpublicationswill

follow relevant external guidance such as the UniformRequirementsforSubmissionofManuscripts toBiomedical

Journals issuedbytheInternationalCommitteeofMedicalJournalEditors(ICMJE)(2008update)andtheCONSORT

statement.36,37

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. Collaboratinginvestigatorswillplayavitalroleindisseminatingtheresultstocolleaguesandpatients.


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Page21of36


The success of the trial will be dependent entirely upon the collaboration of midwives, nurses and doctors in the

participating hospitals and those who hold key responsibility for the trial. Hence, the credit for the study will be

assignedtothekeycollaborator(s) fromaparticipatingsiteas it iscrucialthatthosetakingcreditfortheworkhave

actuallycarrieditout.Theresultsofthetrialwillbereportedfirsttotrialcollaborators.

3.10 FINANCIALSUPPORT

LSHTMisfundingtherunincostsforthistrialandupto2,000patientsrecruitment.Fullfundingisbeingsoughtfrom

publicfundingorganisations. Fundingforthistrialcoversmeetingsandcentralorganisational costsonly. Pfizer,the

manufacturerof tranexamicacid, have provided the funding for the trial drug and placebo used for this trial. The

designandmanagementofthestudyareentirelyindependentofthemanufacturersoftranexamicacid,whichisnota

newproduct.

Largetrialsofsuchdrugs,involvingmanyhospitals,areimportantforfuturepatients,butarepracticableonlyifthose

collaborating in them do so without payment (except for recompense of any minor local costs that may arise).

Agreementforrepaymentoflocalcostswillbemadeinadvance.


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5.Kongnyuy

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6.KhanKS,

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WHO, UNI

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187.

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J.Maternal

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ilkinsC,No

n(UK);2008.

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ternaldeath:

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012002:13

folkD,Tineg

,2007.

tabulation

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rane Datab

terectomies i

ertil2006;34(

gussonD.A

007(4):CD00

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ugs1999;57(

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lity in 2005.

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ssed 11 May

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anisationand

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entralregion

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tet Gynaeco

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babiesduringchildbirth.ClinicalGuidance.RCGOPress,September2007.

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RB,

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Incidence,

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thromboembolism during pregnancy or postpartum: a 30year populationbased study. Ann Intern Med

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30.

Summary

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http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=1489(accessed11th

May,2009).

31. Peto R, Baigent C. Trials: the next 50 years. Large scale randomised evidence of moderate benefits. Bmj

1998;317(7167):11701.

32.HorrowJC,VanRiperDF,StrongMD,GrunewaldKE,ParmetJL.Thedoseresponserelationshipoftranexamicacid.

Anesthesiology1995;82(2):38392.

33. DAMOCLES Study Group. A proposed charter for clinical trial data monitoring committees: helping them to do

theirjobwell.Lancet2005;365(9460):71122.

34.HaybittleJL.Repeatedassessmentofresultsinclinicaltrialsofcancertreatment.BrJRadiol1971;44(526):7937.

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APPENDIX3aBriefinformationleafletforpregnantwomen&family


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APPENDIX3cInformationsheetforwomanandherrepresentative,page1

(HOSPITALLETTERHEAD)

INFORMATIONSHEETFORTHEPATIENTANDHERREPRESENTATIVE(S)

THEWOMANTRIALTITLE OF RESEARCH: TRANEXAMIC ACID FOR THE TREATMENT OF POSTPARTUM HAEMORRHAGE: ANINTERNATIONALRANDOMISED,DOUBLEBLIND,PLACEBOCONTROLLEDTRIAL

TRIALSITENUMBER:[IDfromdatabase]LEAFLETVERSION:VERSION1.0DATED:11MAY2009This hospital is taking part in an international research study to find ways to improve thetreatmentofwomenwhohaveseverebleedingafterdeliveryoftheirbaby.

(1) Wewouldliketoinviteyoutotakepartinthisstudy(2) When you were very unwell you were included in this study and we would like you to

continuetotakepart(3) Asarepresentativeofthepatientweareaskingyoutomakeadecisiononherbehalf

(Pleasecircletheoptionthatapplies)TheResearchDoctorhasalreadycheckedtomakesureyou/thepatientismedicallysuitableforthisresearchandyouarebeingaskedtomakeadecisionaboutwhetheryou/thepatientcanbeincludedinthisstudy.Thissheetgivesinformationaboutthestudy,includingthereasonswhythestudyisbeingdone,andtherisksandbenefitsoftakingpart.

PLEASEREADTHEINFORMATIONBELOWCAREFULLYANDASKTHEDOCTORORMIDWIFELOOKINGAFTERYOUANYQUESTIONSYOUMAYHAVE.

1) Whatisthepurposeofthestudy?

In this hospital, women who have a very severe bleeding after childbirth (also called

postpartum haemorrhage) are given the best available treatments. The aim of thisresearchstudyistoseeifthereisabettertreatmentforwomenwhohaveseverebleeding

afterchildbirth.Wehopethatthetreatment(tranexamicacid)willhelpthebloodtoclotsooner, and so lessen the amount of blood lost and reduce the need for a blood

transfusion and other treatments. But it is also possible that the study treatment may

causeclotswheretheyarenotneeded,andbecausethedrug isnotroutinelyusedafter

childbirth,wedonotknowallthe likelysideeffects. Wehopetofindthatthetreatment

willdoalittlemoregoodthanharmbutwedontyetknowthis.

2) Whyisthisresearchbeingdone?Postpartumhaemorrhagecanbeaveryseriousconditionandsometimesrequiressurgery

to control the bleeding. Many thousands of women worldwide die each year from this

condition and it is important to find better ways of controlling excessive bleeding after

childbirth.

Tranexamic acid is often used to reduce bleeding after major operations such as heart

operations. Some women who have heavy menstrual bleeding (periods) also use

tranexamic

acid.

The

WOMAN

study

is

being

done

to

see

if

TXA

can

reduce

bleeding

in

womenwithpostpartumbleeding.


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Informationsheetforwomanandherrepresentative,page23) Whyhaveyoubeeninvited?

Youhavebeendiagnosedwithpostpartumhaemorrhagebyyourdoctor.Yourdoctorhas

checkedthatyouaresuitableforthestudy,butitisuptoyouwhetherornotyoudecideto

takepart.

4) Who is doing the study and who can you call if you have any questions or

problems?

Dr_____________________________isinchargeofthisstudyatthishospital.Thestudy

is coordinated by doctors and a trial team at The London School of Hygiene & Tropical

Medicine(UniversityofLondon).Ifyouhaveanyquestionsyoucancontactthedoctorat:

Address:

Telephone:

Youarealsofreetovisitthetrialwebsitetokeepuptodatewiththeprogressofthetrial:

www.thewomantrial.Lshtm.ac.uk

5) Apatientcannotbeinthisstudyif: Thedoctorthinksthereisaparticularreasonwhytranexamicaciddefinitelyshouldnotbegiven Thedoctorthinksthereisaparticularreasonwhytranexamicaciddefinitelyshouldbegiven Theyarenotanadult

6) Whatwillhappen/hashappenedduringthisstudy?Youwillbegivenalltheusualemergencytreatmentsforseverebleedingafterchildbirth,

including fluids toreplacetheblood thatyouhave lost. Youwillalsobegivenadoseof

either the tranexamicacidoraplacebo (a liquidwhichdoesntcontain tranexamicacid).

Thisdose

will

be

given

as

an

injection

into

your

vein.

If

after

about

30

minutes

you

are

still

bleeding,orifthebleedingstopsandstartsagainwithin24hoursafterthefirstdose,you

maybegivenaseconddoseofthesame.Youwillnotreceivemorethantwoinjectionsfor

thestudy.

We do not know whether giving tranexamic acid on top of all the other treatments will

helpornot,sohalfthewomeninthestudywillreceivetranexamicacidandtheotherhalf

willreceiveaplacebo. Thechoiceofwhich treatmentyoureceive iscompletelyrandom

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 listatan independent location inLondon. Thestudy involvesnoextra tests

butyour

doctor/midwife

will

send

brief

details

about

your

treatment

and

recovery

to

the

CoordinatingCentre inLondon. Theywillalsosend informationaboutthehealthofy

Woman Protocol

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