triggeredpatcha

ORIGINALRESEARCHARTICLEInvestigationoftheHemostaticEffectofaTransdermalPatchContaining0.
55mgEthinylEstradioland2.
1mgGestodeneComparedwithaMonophasicOralContraceptiveContaining0.
03mgEthinylEstradioland0.
15mgLevonorgestrel:AnOpen-Label,Randomized,CrossoverStudyWolfgangJungeDorisHeger-MahnDietmarTrummerMartinMerzPublishedonline:17September2013TheAuthor(s)2013.
ThisarticleispublishedwithopenaccessatSpringerlink.
comAbstractBackgroundTransdermaldeliveryofcontraceptivesoffersseveraladvantagesovercombinedoralcontracep-tives(COCs),includingeffectiveabsorptionandthepro-visionofrelativelyconstantserumconcentrations.
Ethinylestradiol(EE)andtheprogestingestodenearewell-absorbedthroughtheskinand,therefore,well-suitedforuseinatransdermalcontraceptivepatch.
ObjectiveTheobjectiveofthisstudywastoinvestigatetheimpactofaonce-weeklytransparent,transdermalpatchdeliveringlowdosesofEEandgestodeneequivalenttoaCOCcontaining0.
02mgEEand0.
06mggestodeneonhemostasisparameterscomparedwithamonophasicCOCcontaining0.
03mgEEand0.
15mglevonorgestrel.
MethodsInthissingle-center,open-label,randomized,crossoverstudy,30women(aged18–35years)receivedthreecyclesofeachtreatment,separatedbyatwo-cyclewashoutperiod.
Theprimaryoutcomemeasurewastheabsolutechangefrombaselineinprothrombinfragments12andD-dimer.
ResultsForbothtreatments,prothrombinfragments12remainedstableduringthersttreatmentperiod,andincreasedonlyslightlyinthesecondperiod(meanabsolutechange0.
025and0.
028nmol/LinthenovelBayerpatchandCOCgroups,respectively).
IncreasesinD-dimerwereobservedinbothperiods(meanabsolutechange107.
0±147.
2ng/LforthenovelBayerpatchand113.
7±159.
0ng/LfortheCOC).
Therewerenostatisti-callysignicanttreatmentdifferencesinprothrombin12orD-dimer(p=0.
667andp=0.
884,respectively)andnostatisticallysignicanttreatmentsequenceorperiodeffects.
ConclusionACOCcontaining0.
03mgEEand0.
15mglevonorgestrelandthenovelBayerpatchhavecomparableinuenceonhemostaticendpoints.
Bothtreatmentswerewell-toleratedbysubjects.
1IntroductionThetransdermalapplicationofsteroidhormonesforsys-temicuseisawell-establishedmethodoftherapyinpost-menopausalwomen,usingpatchescontaininganestrogenaloneorincombinationwithaprogestin[1].
Transdermaldeliveryhasalsobeenusedeffectivelyforcontraception.
InEurope,atransdermalcontraceptivepatchwasapprovedin2002thatreleasesethinylestradiol(EE)andnorelgestro-minoverthe7-dayapplicationperiod,resultinginsystemicexposurecomparabletothatobservedafterdailyoraladministrationofacombinedoralcontraceptive(COC)pillcontaining0.
034mgEEand0.
0203mgnorelgestromin[2].
1Morerecently,anovel,once-weeklycontraceptivepatchhasbeendevelopedwithtransparent,transdermaltech-nologytodeliverlowdosesofEEandofgestodenethatresultinthesamesystemicexposureasobservedafteroralW.
JungeLaboratoriumfu¨rKlinischeForschung,Schwentinental,GermanyD.
Heger-MahndinoxFemaleHealthResearch,Berlin,GermanyD.
TrummerM.
Merz(&)BayerPharmaAG,13353Berlin,Germanye-mail:martin.
merz@bayer.
com1IntheUSA,aslightlydifferentformulationwasapprovedbytheUSFDAinNovember2001.
DrugsRD(2013)13:223–233DOI10.
1007/s40268-013-0028-2administrationofaCOCcontaining0.
02mgEEand0.
06mggestodene(BayerPharmaAG,unpublisheddata).
Whiledailyoralcontraceptives—currentlythemostcommonformofcontraceptionusedbywomeninthedevelopedworld[3]—arehighlyefcaciouswhenusedcorrectly,poorcomplianceisacommonproblem,andcanresultingreatlyreducedefcacy[4].
Furthermore,oraladministrationmaybeassociatedwithrapidandlargeuctuationsinserumconcentrations[5],thebioavailabilityofEEislow(38–48%)[6],andtheuseofCOCscanalsoresultinlargeintra-andinter-individualpharmacokineticvariabilityinserumlevels[7].
Transdermaldeliveryoffersseveraladvantagesovertheoraladministrationofhor-mones,includingeffectiveabsorptionandtheprovisionofrelativelyconstantserumconcentrations[5,8].
Theseadvantages,inconjunctionwiththeconvenienceofweeklypatchapplication,whichmayincreasecompliance,suggestthattransdermalhormonedeliverymayconstituteanattractiveoptionforwomenwhopreviouslyfelttheircontraceptivechoicewaslimited.
BothEEandgestodenearehormonesthatarewell-absorbedthroughtheskin.
Consequently,theyareappro-priatefortransdermaldelivery[5,8].
Atpresent,EEisthemostpotentestrogenagonistavailable[9],anditsuseinCOCsiswell-documented.
Gestodeneisawell-researchedprogestin,withestablishedefcacyandsafety,andhasbeenwidelyusedasacontraceptiveagentinEuropeformorethan20years[10–12].
Furthermore,thegoodskinabsorptionpropertiesofgestodene[13],andthelowabsolutedoserequiredforcontraceptiveefcacy[14],allowforasmallpatchsize(BayerPharmaAG,unpub-lisheddata).
Anincreasedriskofvenousthromboembolism(VTE)hasbeenreportedwithuseofCOCs.
ThisriskhasbeenattributedpredominantlytoEE-inducedchangesintheconcentrationofcoagulatoryandbrinolyticproteins,aswellaschangesinplateletactivity[15].
UsingalowerdoseofEEmayhelptoamelioratethisriskandreducetheadverseeffectsassociatedwiththeestrogencomponentofCOCs[16].
WhilethereissomeevidencethatCOCscontaininglowerdosesofEEareassociatedwithfewernegativehemostaticeffects[17],theroleofthird-genera-tionprogestinsconstitutesasourceofcontinuingdebate.
AlthoughtherehavebeenattemptstopredictVTEriskthroughtheevaluationofchangesoccurringinthecoagu-latorysystem,thesesurrogateparametersarenotgenerallyaccepted.
However,analysisoftheseparametersisrequiredbytheguidelinesforthedevelopmentofsteroidalcontraceptives[18].
Ingeneral,theeffectofthird-genera-tionCOCsoncoagulatorymechanismsappearstobeminimal,reectingabalancebetweenthestimulationofboth(pro)coagulantandbrinolyticfactors[19].
Despitethesendings,therearedatatosuggestthatthird-genera-tionCOCscanhaveasubstantialeffectonhemostaticbalance,andmayresultinaprothromboticstateamongusers.
Indeed,therearereportsthatwomenusingthird-generationCOCsaresignicantlylesssensitivetoacti-vatedproteinC(APC)thanwomenusingsecond-genera-tionformulations(p.
001);itcouldbespeculatedthatthesedifferencesmaycorrelatewithahigherriskofthrombosisinthird-generationCOCusers[20].
Further-more,forboththird-andsecond-generationformulations,COC-inducedincreasesintheactivityof(pro)coagulatoryfactorsarenotalwaysbalancedbyincreasedbiologicallevelsofcoagulationinhibitors[21].
Thereissomeindi-cationthattransdermaldeliveryofhormonesmayreducetheriskofVTEassociatedwithCOCuse[22],althoughthesupportingdataarelimited,andresultsfromclinicaltrialsareconicting[16,23–25].
Tofurtherinvestigatetheeffectoftransdermaldeliveryonhemostaticparameters,weconductedanopen-label,randomized,crossoverstudyofthenovelBayerpatchincomparisontoamonophasicCOCcontaining0.
03mgEEand0.
15mglevonorgestrel.
2MaterialsandMethods2.
1ObjectivesandStudyDesignTheprimaryobjectiveofthisstudywastoinvestigatetheimpactofthenovelBayerpatch(patchsize11cm2;con-taining0.
55mgEEand2.
1mggestodeneperpatch)onhemostasisparametersina21-dayregimenoveratreat-mentperiodofthreecycles,comparedwithastandard,monophasicCOCcontaining0.
03mgEEand0.
15mglevonorgestrelpertablet(Microgynon,BayerHealthcareAG,Germany).
Secondaryobjectivesincludedassessmentofsafety,contraceptiveefcacy,bleedingpattern,andcyclecontrol.
Thiswasanopen-label,randomized,crossoverstudyconductedatasinglecenterinGermany(ClinicalTri-als.
govidentier:NCT00933179).
Thestudywascon-ductedinaccordancewiththeDeclarationofHelsinki,theInternationalConferenceonHarmonisationGuidelineonGoodClinicalPractice,andlocallaws.
ThedesignofthestudyadherestotherequirementsoftheEuropeanMedi-cinesAgencyCommitteeforMedicinalProductsforHumanUseguidelineonclinicalinvestigationofsteroidcontraceptivesinwomen(EMEA/CPMP/EWP/519/98Rev1)[18].
Thestudyprotocolwasapprovedbyacom-petentEthicsCommitteeinBerlin,Germany.
Informedconsentwasobtainedfromeachsubjectbeforeentryintothestudy.
224W.
Jungeetal.
2.
2ParticipantsThisstudyrecruitedhealthywomen,18-35yearsofage,whorequiredcontraceptionandwhohadanormalcervicalsmearresulteitheratscreeningordocumentedinthelast6months,andahistoryofregularcyclicmenstrualperiods.
Womenwereexcludediftheywerepregnantorlactating,orhadfewerthanthreemenstrualcyclessincedelivery,abortion,orlactationpriortothestartoftreatment.
Othermainexclusioncriteriaincludedtheuseofothermethodsofcontraception;undiagnosedabnormalgenitalbleeding;obesity[bodymassindex(BMI)[30.
0kg/m2];knownhypersensitivitytoanyofthestudydrugs;anydisease,condition,oruseofmedicinesthatcouldinterferewiththestudymedication;oranydiseaseorconditionthatcouldworsenunderhormonaltreatment.
2.
3StudyTreatmentSubjectswererandomized(1:1)intooneoftwotreatmentsequences,usingacomputer-generatedrandomizationlist.
TreatmentsequenceA:administrationofthreecyclesofthenovelBayerpatch(treatmentperiod1)followedbytwowashoutcyclesandthenadministrationofthreecyclesofCOC(treatmentperiod2);ortreatmentsequenceB:administrationofthreecyclesofCOC(treatmentperiod1)followedbytwowashoutcyclesandthenadministrationofthreecyclesofthenovelBayerpatch(treatmentperiod2)[Fig.
1].
TreatmentwiththenovelBayerpatchconsistedofa21-dayregimenadministeredaspartofeach28-daycycle(onepatchperweekfor3weeksfollowedbya7-day,patch-freeinterval)forthreecycles.
Eachsubsequentcyclestartedimmediatelyaftertheendofthepatch-freeintervalofthepreviouscycleandwasnottriggeredbythepresenceorabsenceofuterinebleeding.
Onlyonepatchwaswornatatimeandwasself-appliedbythesubjecttotheouterupperarm,abdomen,orbuttocks.
Withinanygivencycle,thethreepatcheswereappliedtothesameapplicationsite;subjectswerepermittedtoswitchbetweentheleftandrightsideofanychosenapplicationsite(e.
g.
,leftorrightouterupperarms).
Applicationsitescouldvaryfromcycletocycle.
ForCOCuse,onetabletwastakendailyfor21consecutivedays,witheachsubsequentpackstartingaftera7-day,tablet-freeinterval.
Duringthewashoutcycles,subjectswererequiredtousenon-hormonalcontraception;condoms,spermicide,ordiaphragmwerepermitted,butnotthecalendarortemperaturemethods.
2.
4ScheduleofVisitsThescreeningvisit(visit1)wasperformedwithin12weekspriortothestartofthetreatmentcycle.
Beforethestartoftreatment,twowashoutcycles(1and2)wererequired.
Visit2tookplaceduringwashoutcycle2(days15–21).
Visit3tookplaceduringtreatmentcycle3(days15–21)intreatmentperiod1.
Beforethenexttreatmentperiod,anothertwowashoutcycles(3and4)wererequired.
Visits4and5tookplaceduringwashoutcycles3and4(days15–21),respectively.
Visit6tookplaceduringtreatmentcycle6(days15–21)intreatmentperiod2.
Afollow-upvisittookplace21–28daysaftertheremovalofWashoutcycles1–2aV1SOTEOTEOTSOTV2V3V4V5V6V7Washoutcycles3–4Period1Treatmentcycles1–3NovelBayerPatchNovelBayerPatchSequenceAbCOCCOCSequenceBcPeriod2Treatmentcycles4–6Fig.
1Studyoverview.
aIfthesubjectisahormonalcontraceptivestarter(i.
e.
,hasnotusedhormonalcontraceptivesforaperiodof3monthsbeforestartingthestudy),nowashoutperiodwasnecessary;bTreatmentsequenceA:novelBayerpatchcontaining0.
55mgEEand2.
1mgGSDinperiod1,COCcontaining0.
03mgEEand0.
15mgLNGinperiod2;cTreatmentsequenceB:COCcontaining0.
03mgEEand0.
15mgLNGinperiod1,novelBayerpatchcontaining0.
55mgEEand2.
1mgGSDinperiod2.
COCcombinedoralcontraceptive,EEethinylestradiol,EOTendoftreatment,GSDgestodene,LNGlevonorgestrel,SOTstartoftreatment(ontherstdayofbleeding),V1screeningvisit,V2baseline–washoutcycle2(days15–21),V3treatmentperiod1–treatmentcycle3(days15–21),V4washoutcycle3(days15–21),V5washoutcycle4(days15–21)orbaselinefortreatmentperiod2,V6treatmentperiod2–treatmentcycle6(days15–21),V7upto2weeksafterEOT,butatleast2daysaftertheendofthewithdrawalbleedingthatfollowstreatmentcycle6HemostaticEffectofaTransdermalPatchvs.
aCombinedOralContraceptive225thelastpatchorintakeofthelasttablet(seeFig.
1foranoverview).
2.
5PrimaryandSecondaryVariablesTheprimaryobjectiveofthisstudywastoinvestigatetheimpactofthetwotreatmentsonhemostasisparameters.
Theprimaryvariablesselectedassensitiveactivationmarkersforcoagulationstatusweretheabsolutechangesinprothrombinfragments12andD-dimerfollowingthreetreatmentcycleswiththenovelBayerpatchandCOC,respectively.
Laboratoryassessmentofprothrombinfrag-ments12wasmadeusingEnzygnost12(Siemens,Munich,Germany),andD-dimervalueswereassessedusingAsserachromD-dimer(RocheDiagnostics,Basel,Switzerland).
Secondaryvariablesconsistedof(pro)coagulatoryparameters(brinogen,FactorII,FactorVII,andFactorVIIIactivity)andanti-coagulatoryparameters(anti-thrombinIII,proteinC,andproteinS).
APCresistancewasdeterminedusingCOATESTreagents(HaemochromDiagnostica,Essen,Germany).
TheAPCsensitivityratiowasmeasuredbythemethoddescribedbyRosingetal.
[20].
Bloodsamplesweretakenafterminimalobstructionoftheupperarmandimmediatereleaseaftervenepunctureattheforearm.
Subjectswererequiredtorestinasupinepositionandtoadheretoafastingperiodofatleast12hpriortothecollectionofbloodsamples.
Thenumbersofbleedingandspotting,bleeding-only,andspotting-onlydayswererecordedtodeterminebleed-ingpattern,andwomenkeptadailyrecordofmenstrualbleedingintensity.
Toanalyzecyclecontrol,menstrualbleedingwasclassiedaswithdrawalbleeding(followingscheduledtreatmentwithdrawal),applicationdeviationbleeding(followingunscheduledtreatmentwithdrawal),orintracyclicbleeding(other).
2.
6OtherEfcacyVariablesWithregardtothenumberofunintendedpregnancies,allpregnanciesthatoccurredduringthestudyuntil7daysafterremovalofthelastpatchwererecorded.
2.
7OtherSafetyVariablesOtherlaboratoryassessmentsconductedincludehematol-ogy,plasmachemistry,liverenzymes,sexhormone-bindingglobulin,andcarbohydrateandlipidmetabolism.
Adverseeventswereassessedthroughoutthestudyforeachtreatment.
Othersafetyparametersincludedgyneco-logicalndings,vitalsigns,bodyweight,BMI,andcer-vicalsmearresults.
2.
8TreatmentComplianceWomenwererequiredtorecordthenumberofCOCtablets(0,1,or2)takeneachday,thedatesnewpatcheswereapplied,thepatchapplicationsite,patchapplicationdevi-ations,thereasonforpatchremoval(ifapplicable),thedatestheydidnotwearapatch,andwhetherback-upcontraceptionwasused.
Patchadhesion(e.
g.
,thenumberofcompletelyandpartiallydetachedpatchespercycle)wasalsorecorded.
2.
9StatisticalAnalysesAlltreatmentvariableswereanalyzedusingdescriptivestatisticalmethods.
Theprimaryanalysesofthisstudywereperformedontheabsolutechangesfromcorrespondingbaselinevaluesforthetwoprimaryvariables(prothrombinfragments12andD-dimer).
Anormaldistributionwasassumedfortheabsolutechangeineachparameter.
ThetreatmenteffectineithervariablewasinvestigatedusinganANOVAmodeltotestforatreatmentdifferenceforeachvariable.
Bonferronicorrectionwasusedtoaccountformultipletesting;therefore,foreachofthetwoprimaryhemostaticparameters,a97.
5%two-sidedcon-denceintervalwasderivedforthetreatmentdifference.
Forthesecondaryvariables,descriptiveanalysesoftheabso-luteandrelativechangesfromcorrespondingbaselinevalueswereconducted.
Whileasamplesizeof30womenwaschosenwithoutformalstatisticalpowerconsiderations,thisnumberiscommonlyusedformetabolicstudiesoncontraceptives.
Allwomenwhoreceivedstudydrug,andforwhomdatafromanytreatmentperiodwereavailable,wereincludedinthefullanalysisset(FAS).
TheprimaryanalysisofthisstudywasbasedontheFAS;thispopulationwasalsousedforevaluationofsafetydata.
3Results3.
1SubjectDispositionandDemographicsAtotalof48womenwereenrolledontothestudy.
Ofthesewomen,18didnotpassthescreeningprocess,and30wererandomizedfortreatment(Fig.
2).
Intotal,15womenwereassignedtoeachoftreatmentsequencesAandB.
Onewomanchosetowithdrawfromthestudypriortotreatment(sequenceB),and29womeneitherstartedtreatmentor,forthosewhohadusedamethodofhormonalcontraceptionpriortoscreening,performedtherstwashoutphaseandthenstartedtreatmentperiod1.
Forvewomenintreat-mentsequenceAandthreewomenintreatmentsequenceB,previoususeofhormonalcontraceptionwasreported226W.
Jungeetal.
andarstwashoutphaserequired.
All29womencom-pletedtreatmentperiod1andthesecondwashoutphase;these29womenconstitutetheFAS.
Duringthesecondwashoutphase,aftertreatmentwiththeCOC,onewomanintreatmentsequenceBbecamepregnantanddiscontinuedthestudy.
Theremaining28womenstartedtreatmentperiod2,whichwascompletedbyatotalof26subjects:13subjects(86.
7%)intreatmentsequenceAand13subjectsScreeningfailures/non-randomizedn=18RandomizedtosequenceAn=15RandomizedtosequenceBn=151stwashoutn=151stwashoutn=14Nevertookdrugn=1Period1:treatmentstartedwithNovelBayerPatchn=15Period1:treatmentstartedwithCOCn=14Period1:treatmentcompletedawithNovelBayerPatchn=15Period1:treatmentcompletedawithCOCn=14Period2:treatmentstartedwithCOCn=15Period2:treatmentstartedwithNovelBayerPatchn=13Period2:treatmentcompletedawithCOCn=13Period2:treatmentcompletedawithNovelBayerPatchn=13Studycompletedbn=13Studycompletedbn=132ndwashoutstartedn=152ndwashoutstartedn=14Studydiscontinuedn=1Pregnancy1Studydiscontinuedn=2Losttofollow-up1Protocoldeviation1Enrolledn=48Fig.
2Dispositionofsubjects.
aSubjectsusingthenovelBayerpatchwereregardedashavingcompletedtreatmentiftherewereC77daysbetween'Lastdaypatchremoved'and'Firstdaypatchworn'inperiod2;bThestudywascompletedonlyifthesubjecthadcompletedthetreatmentperiodandhadperformedthefollow-upvisit.
COCcombinedoralcontraceptiveHemostaticEffectofaTransdermalPatchvs.
aCombinedOralContraceptive227(92.
9%)intreatmentsequenceB.
Twosubjectsdiscon-tinuedthisperiodprematurely:onewaslosttofollow-up,andtheotherdiscontinuedfollowingaprotocoldeviation.
ThekeydemographiccharacteristicsoftheFASpopu-lationaresummarizedinTable1.
Overall,characteristicswereverysimilarbetweenthetreatmentgroups.
3.
2PrimaryHemostasisParametersWithregardtoprothrombinfragments12,nostatisti-callysignicantdifferenceswereobservedbetweenthetreatmentgroupsineithertreatmentperiod.
Whilelittlechangewasobservedinthersttreatmentperiod,anincreaseofprothrombinfragments12wasseeninthesecondtreatmentperiodforbothgroups(baselinevalues0.
099and0.
109nmol/LinthenovelBayerpatchandCOCgroups,respectively;absolutechanges0.
025and0.
028nmol/LinthenovelBayerpatchandCOCgroups,respectively).
Overbothtreatmentperiods,theoverallmeanabsolutechangewas0.
008±0.
042nmol/LforthenovelBayerpatchgroupand0.
013±0.
043nmol/LfortheCOCgroup;thetreatmentdifferenceof0(two-sided97.
5%CI-0.
032to0.
022)wasnotstatisticallysignicant(p=0.
667).
Therewerenostatisticallysignicanttreat-mentsequenceorperiodeffects.
SlightdifferencesinD-dimerconcentrationswereobservedbetweenthetreatmentgroupsinbothtreatmentperiods;however,thesewerenotstatisticallysignicant.
Overbothtreatmentperiods,theoverallmeanabsolutechangewas107.
0±147.
2ng/LforthenovelBayerpatchgroupand113.
7±159.
0ng/LfortheCOCgroup.
Thetreatmentdif-ferenceof-6.
19(two-sided97.
5%CI-103.
00to90.
92)wasnotstatisticallysignicant(p=0.
884).
3.
3SecondaryVariablesAsummaryoftheabsolutechangesinthesecondarycoagulationparametersisshowninTable2.
Noneofthesechangeswasofclinicalorfunctionalsignicance.
3.
4OtherEfcacyVariables3.
4.
1CycleControlIntheFAS,withdrawalbleedingwasexperiencedby86.
7–100%ofwomeninalltreatmentcyclesusingthenovelBayerpatch,andby83.
3–100%ofwomenusingtheCOC,whileintracyclicspotting/bleedingwasreportedby6.
7–30.
8and7.
1–25.
0%ofwomeninalltreatmentcycles,respectively.
3.
4.
2ContraceptiveEfcacyAlthoughsubjectswerewell-informedandconrmedthattheywouldusenon-hormonalmethodsofcontraception(condomswereofferedanddistributedthroughoutthestudy),onewomanbecamepregnantduringthesecondwashoutphasefollowingtreatmentperiod1,duringwhichthewomanhadtakentheCOC.
Allotherpregnancytestresultsduringthecourseofthestudywerenegative.
3.
5SafetyDuetothecrossoverdesignofthestudy,adverseeventswererecordedpertreatmentregardlessoftreatmentsequence.
Atleastonetreatment-emergentadverseeventwasreportedby21women(72.
4%)usingthenovelBayerTable1Subjectdemographicsandbaselinecharacteristics(fullanalysisset)fortreatmentsequenceA(n=15),treatmentsequenceB(n=14),andintotal(n=29)TreatmentsequenceAaTreatmentsequenceBbTotalCharacteristic[mean±SD(range)]Age(years)26.
9±5.
3(18–35)27.
2±3.
8(18–32)27.
0±4.
6(18–35)Height(cm)167.
3±4.
5(161–174)166.
8±7.
2(148–178)167.
1±5.
8(148–178)Bodyweight(kg)62.
6±7.
0(51–78)62.
5±9.
0(44–78)62.
6±7.
9(44–78)BMI(kg/m2)22.
4±2.
4(19–26)22.
4±2.
8(19–29)22.
4±2.
6(19–29)Race[n(%)]Caucasian14(93.
3)13(92.
9)27(93.
1)Asian1(6.
7)1(7.
1)2(6.
9)BMIbodymassindex,COCcombinedoralcontraceptive,EEethinylestradiol,GSDgestodene,LNGlevonorgestrel,SDstandarddeviationaTreatmentsequenceA=transdermalpatchcontaining0.
55mgEEand2.
1mgGSDinperiod1,COCcontaining0.
03mgEEand0.
15mgLNGinperiod2bTreatmentsequenceB=COCcontaining0.
03mgEEand0.
15mgLNGinperiod1,transdermalpatchcontaining0.
55mgEEand2.
1mgGSDinperiod2228W.
Jungeetal.
Table2Summaryofabsolutechangesinsecondarycoagulationparameters(fullanalysisset)ParametersNovelBayerpatchaCOCbncMeanSDncMeanSDPrimaryhemostasisparametersProthrombinfragments12(nmol/L)[referencerange0.
07–0.
23nmol/L]dPeriod1:baseline150.
10.
0140.
10.
0Period1:treatmentcycle3150.
10.
1140.
10.
1Period1:absolutechange(baselinetocycle3)150.
00.
0140.
00.
1Period2:baseline130.
10.
0140.
10.
0Period2:treatmentcycle3130.
10.
1130.
10.
0Period2:absolutechange(baselinetocycle3)130.
00.
0130.
00.
0Bothperiodstogether:absolutechange(baselinetocycle3)280.
00.
0270.
00.
0D-dimer(nmol/L)[referencerange0.
0–500nmol/L]ePeriod1:baseline15174.
155.
414164.
266.
2Period1:treatmentcycle315269.
5185.
414268.
0179.
6Period1:absolutechange(baselinetocycle3)1595.
3172.
814103.
8150.
2Period2:baseline13145.
585.
714164.
947.
7Period2:treatmentcycle313265.
9146.
413289.
5180.
5Period2:absolutechange(baselinetocycle3)13120.
5116.
613124.
4173.
5Bothperiodstogether:absolutechange(baselinetocycle3)28107.
0147.
227113.
7159.
0Thrombinandbrinturnover(activationmarker)Prothrombin(FactorII)(%)[referencerange70–120%]Period1:baseline1599.
910.
014113.
413.
2Period1:treatmentcycle315117.
28.
414114.
911.
3Period1:absolutechange(baselinetocycle3)1517.
311.
7141.
513.
5Period2:baseline13101.
215.
614101.
410.
1Period2:treatmentcycle313118.
111.
613110.
513.
2Period2:absolutechange(baselinetocycle3)1316.
915.
0139.
07.
2Baseline(bothperiodstogether)28100.
512.
728107.
413.
1Absolutechange(bothperiodstogether)2817.
113.
1275.
111.
4(Pro)coagulatoryparametersFibrinogen(g/L)[referencerange1.
8–3.
5g/L]Period1:baseline152.
70.
5142.
70.
5Period1:treatmentcycle3152.
70.
6143.
01.
0Period1:absolutechange(baselinetocycle3)150.
00.
7140.
20.
9Period2:baseline132.
40.
6142.
30.
5Period2:treatmentcycle3132.
70.
8132.
50.
4Period2:absolutechange(baselinetocycle3)130.
30.
7130.
20.
4Baseline(bothperiodstogether)282.
60.
5282.
50.
5Absolutechange(bothperiodstogether)280.
20.
7270.
20.
7FactorVIIactivity(%)[referencerange70–120%]Period1:baseline1590.
518.
914109.
119.
6Period1:treatmentcycle315112.
016.
614105.
917.
6Period1:absolutechange(baselinetocycle3)1521.
515.
514-3.
216.
8Period2:baseline1392.
917.
61496.
917.
1Period2:treatmentcycle313118.
417.
21397.
716.
3Period2:absolutechange(baselinetocycle3)1325.
512.
2133.
47.
9Baseline(bothperiodstogether)2891.
618.
028103.
019.
1Absolutechange(bothperiodstogether)2823.
314.
0270.
013.
5HemostaticEffectofaTransdermalPatchvs.
aCombinedOralContraceptive229Table2continuedParametersNovelBayerpatchaCOCbncMeanSDncMeanSDFactorVIIIactivity(%)[referencerange70–150%]Period1:baseline1590.
19.
91488.
717.
6Period1:treatmentcycle31599.
09.
51496.
422.
5Period1:absolutechange(baselinetocycle3)158.
911.
3147.
711.
8Period2:baseline1390.
918.
41489.
412.
8Period2:treatmentcycle31396.
021.
41394.
513.
7Period2:absolutechange(baselinetocycle3)135.
19.
8134.
210.
2Baseline(bothperiodstogether)2890.
514.
22889.
115.
1Absolutechange(bothperiodstogether)287.
110.
6276.
011.
0Anti-coagulatoryparametersAnti-thrombinIIIactivity(%)[referencerange75–125%]Period1:baseline1597.
29.
31497.
610.
2Period1:treatmentcycle31598.
87.
51499.
67.
0Period1:absolutechange(baselinetocycle3)151.
67.
8142.
06.
8Period2:baseline1398.
96.
31499.
64.
4Period2:treatmentcycle31396.
88.
51396.
96.
1Period2:absolutechange(baselinetocycle3)13-2.
14.
713-1.
95.
7Baseline(bothperiodstogether)2898.
07.
92898.
67.
8Absolutechange(bothperiodstogether)28-0.
16.
7270.
16.
5ProteinCactivity(%)[referencerange70–150%]Period1:baseline15102.
417.
814106.
115.
5Period1:treatmentcycle315106.
113.
314111.
917.
0Period1:absolutechange(baselinetocycle3)153.
710.
6145.
711.
4Period2:baseline13101.
919.
51497.
711.
0Period2:treatmentcycle313114.
020.
713103.
212.
3Period2:absolutechange(baselinetocycle3)1312.
18.
4137.
310.
2Baseline(bothperiodstogether)28102.
218.
328101.
913.
9Absolutechange(bothperiodstogether)287.
610.
4276.
510.
6ProteinSactivity(%)[referencerange52–118%]Period1:baseline1580.
911.
71474.
611.
8Period1:treatmentcycle31577.
710.
11481.
29.
0Period1:absolutechange(baselinetocycle3)15-3.
16.
9146.
612.
8Period2:baseline1379.
79.
01482.
69.
2Period2:treatmentcycle31370.
610.
61382.
910.
4Period2:absolutechange(baselinetocycle3)13-9.
15.
413-0.
39.
3Baseline(bothperiodstogether)2880.
310.
32878.
611.
2Absolutechange(bothperiodstogether)28-5.
96.
8273.
311.
6APCresistance(ratio)[referencerange2.
0–5.
0]Period1:baseline153.
10.
3143.
20.
5Period1:treatmentcycle3153.
00.
4143.
00.
4Period1:absolutechange(baselinetocycle3)15-0.
10.
414-0.
20.
3Period2:baseline133.
30.
6143.
20.
3Period2:treatmentcycle3132.
90.
4133.
10.
4Period2:absolutechange(baselinetocycle3)13-0.
40.
213-0.
10.
2Baseline(bothperiodstogether)283.
20.
5283.
20.
4Absolutechange(bothperiodstogether)28-0.
20.
327-0.
10.
3230W.
Jungeetal.
patchand18(62.
1%)usingtheCOC;theseweremostfrequentlynasopharyngitis[13(44.
8%)and12(41.
1%)women,respectively]andheadache[4(13.
8%)and3(10.
3%)women,respectively].
Twelveeventswerecon-sideredtobetreatmentrelated,andwereexperiencedbyvewomen(17.
2%)inthenovelBayerpatchgroupandtwo(6.
9%)intheCOCgroup.
Allweremildtomoderateinintensity.
Nowomendiscontinuedthestudyprematurelyduetoadverseeventsandnoseriousadverseeventsordeathswerereported.
3.
6TreatmentComplianceOverall,compliancewiththenovelBayerpatchwasgood,withwomenwearingthepatchanestimated99.
9%(±0.
38;range98.
5–100.
0)oftherequired21days.
Com-pliancewithCOCtreatmentwasalsogood,withanesti-mated98.
6%ofwomen(±2.
50;range90.
5–100.
0)takingtheexpected63tabletsoverthreecycles.
4DiscussionTheaimofthiscrossoverstudywastoexaminetheimpactofthenovelBayerpatchandaCOConprothrombinfragments12andD-dimerinhealthywomenovertwotreatmentperiods,eachcomprisingthreetreatmentcycles.
Theaforementionedhemostasisparameterswereselectedbecausetheyaresensitiveindicatorsofcoagulationandbrinolysisactivation;thecomparatorCOCwaschosenasagold-standard,referencemonophasicCOCtocomplywiththeEuropeanMedicinesAgencyCommitteeforMedicinalProductsforHumanUseguidelineonclinicalinvestigationofsteroidcontraceptivesinwomen,whichstatesthataproductcontaininglevonorgestrelandEE(150/30lg)ordesogestrelandEE(150/30lg)isappro-priateasacomparatorwhereVTEriskhasbeenestablishedinobservationalstudies[18].
Whileprothrombinfragment12levelswerestable(rsttreatmentperiod)orslightlyincreased(secondtreat-mentperiod)inresponsetobothtreatments,increasesinD-dimerwereobservedunderbothtreatmentsandinbothtreatmentperiods;however,thedifferencesinthechangesbetweentreatmentgroupswereneitherstatisticallynorclinicallysignicant.
TheobservedincreaseforD-dimerinbothtreatmentperiods,andforprothrombinfragments12inthesecondperiod,impliesthattheoverallbalancebetweenthedifferentfactorsinuencinghemostasiswasmaintainedonanincreasedlevel.
Withregardtochangesinthesecondaryhemostasisparameters,bothtreatmentsshowedaslightincreaseinactivationmarkerlevels;however,inmostcases,theseincreasedvaluesdidnotexceedtheirupperreferencelimits.
Therewereno,orminimal,changesin(pro)coag-ulatoryfactorswitheithertreatment,exceptforFactorVIIactivity,whichincreasedinbothtreatmentperiodswiththenovelBayerpatch.
Inbothtreatmentsequences,thebal-anceofthecoagulatorysystemappearedtobemaintainedatanincreasedlevelforboththepro-andtheanti-coagu-latoryparameters.
Thisisconsistentwithanincreaseinbrinturnover.
Itisdifculttocorrelatechangesinindividualhemos-tasisparameterswiththeclinicalendpointofVTE.
Com-parativepharmacodynamicsdatamayindicatepossibleTable2continuedParametersNovelBayerpatchaCOCbncMeanSDncMeanSDAPCsensitivity(ratio)[referencerange0.
9–2.
2]Period1:baseline152.
00.
9142.
41.
3Period1:treatmentcycle3153.
71.
1144.
51.
4Period1:absolutechange(baselinetocycle3)151.
70.
6142.
11.
0Period2:baseline132.
31.
4141.
80.
9Period2:treatmentcycle3134.
81.
4133.
31.
2Period2:absolutechange(baselinetocycle3)132.
60.
8131.
40.
8Baseline(bothperiodstogether)282.
11.
2282.
11.
2Absolutechange(bothperiodstogether)282.
10.
8271.
81.
0APCactivatedproteinC,COCcombinedoralcontraceptive,EEethinylestradiol,GSDgestodene,LNGlevonorgestrel,SDstandarddeviationaNovelBayerpatch=0.
55mgEEand2.
1mgGSDbCOC=0.
03mgEEand0.
15mgLNGcn=totalnumberofsubjectswhoreceivedtreatment.
Note:subjectstreatedinperiod1aredifferentfromthosetreatedinperiod2dTreatmentdifference=0.
0,two-sided97.
5%CI:0.
0–0.
0,pvalueoftestfortreatmentdifference=0.
667eTreatmentdifference=-6.
2,two-sided97.
5%CI:-103to90.
9,pvalueoftestfortreatmentdifference=0.
884HemostaticEffectofaTransdermalPatchvs.
aCombinedOralContraceptive231differencesbetweenproducts,buttherearenogenerallyacceptedsurrogateendpointsfortheriskofVTE[18].
Asexpected,theevaluationofboththeprimaryandsecondaryparametersinthisstudyshowsthatindividualhemostasisparametersarechangedbybothtreatments.
Thishasbeenwell-documentedforotherlow-dosecombinedhormonalcontraceptives[26–28].
Overall,thesimultaneouschangesinpro-andanti-coagulatoryparametersseeninthisstudydonotsuggestadifferenceinVTErateforthenovelBayerpatchcomparedwithcurrentlymarketedlow-doseCOCs.
Theproleofadverseeventsrecordedduringthecourseofthestudyindicatedthatbothtreatmentswerewell-tolerated.
Inaddition,nosafetyeventsofclinicalsigni-cancewereobserved,andbleedingpatternandcyclecontrolwere,ingeneral,comparablebetweenthetwotreatments.
BoththenovelBayerpatchandtheCOCshowedgoodcontraceptiveefcacyinthisstudy,withnopregnanciesoccurringduringeithertreatment.
Onepregnancyoccurredduringthesecondwashoutphaseofthisstudy;however,thisoccurredafterintakeofthelastCOCtablet.
Despitethesefavorableresults,cautionshouldbetakenwheninterpretingthesendingswiththeaimofpredictingVTEriskamongusersofdifferenthormonalcontracep-tives.
Althoughcomparativepharmacodynamicdatamaybeusedtoindicatepossibledifferencesbetweenproducts,therearenogenerallyacceptedsurrogateendpoints.
Inaddition,itshouldalsobenotedthattheinabilityofthisstudytondanydifferencesbetweentreatmentsmaybeareectionofitssmallsamplesizeandrelativelyshorttreatmentduration.
Inadditionlipidmetabolismwasnotassessedinthepresentstudy.
However,studydatahaveshownthatlow-densitylipoproteincholesterollevels(LDL-C)decreaseandtriglycerideandhigh-densitylipo-proteincholesterol(HDL-C)levelsincreasefrombaselinelevelsaftertreatmentwithacontraceptivepreparationthatcontainsgestodeneandEE.
ThesechangesresultedinanincreasedHDL-C/LDL-Cratio,demonstratingthatthecontraceptivehadananti-atherogeniceffect[29].
5ConclusionTheresultsofthiscrossover,comparativestudydemon-stratethatboththenovelBayerpatchdeliveringlowdosesofEEandgestodeneandalow-dose,monophasicCOCcontainingEEandlevonorgestrelhavecomparableinu-enceonhemostaticendpoints.
Bothtreatmentswerewell-toleratedbysubjects,andnoclinicallysignicantlabora-torychangeswereobserved.
AcknowledgmentsThestudywasfundedbyBayerPharmaAG.
StatisticalsupportwasprovidedbyMrKeithFalconerandMrFlorianHiemeyer.
EditorialassistancewasprovidedbyOgilvy4D,Oxford,UK,andwasfundedbyBayerPharmaAG.
ProfessorJungehasnonancialinvolvementstodisclose.
DrHeger-MahnhasreceivedresearchfundingfromBayerPharmaAG.
MrTrummerandDrMerzareemployeesofBayerPharmaAG.
OpenAccessThisarticleisdistributedunderthetermsoftheCreativeCommonsAttributionNoncommercialLicensewhichper-mitsanynoncommercialuse,distribution,andreproductioninanymedium,providedtheoriginalauthor(s)andthesourcearecredited.
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