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Efficacy and safety of vaginally administered lyophilized Lactobacillus crispatus IP 174178 in the prevention of bacterial vaginosis recurrence

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Efficacy and safety of vaginally administered lyophilized

Lactobacillus crispatus IP 174178 in the prevention of

bacterial vaginosis recurrence

J. M. Bohbot, E. Darai, F. Bretelle, G. Brami, C. Daniel, J. M. Cardot

To cite this version:

J. M. Bohbot, E. Darai, F. Bretelle, G. Brami, C. Daniel, et al.. Efficacy and safety of vaginally

administered lyophilized Lactobacillus crispatus IP 174178 in the prevention of bacterial vaginosis

recurrence. Journal of Gynecology Obstetrics and Human Reproduction, Elsevier, 2018, 47 (2),

pp.81-86. �10.1016/j.jogoh.2017.11.005�. �hal-01791646�

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Review

Efficacy

and

safety

of

vaginally

administered

lyophilized

Lactobacillus

crispatus

IP

174178

in

the

prevention

of

bacterial

vaginosis

recurrence

J.M.

Bohbot

a

,

E.

Daraı¨

b

,

F.

Bretelle

c

,

G.

Brami

d,

*

,

C.

Daniel

d

,

J.M.

Cardot

e

aInstitutAlfred-Fournier,75014Paris,France

bServicedegyne´cologie-obste´triqueetme´decinedelareproduction,hoˆpitalTenon,universite´ Pierre-et-Marie-Curie,UMRS938,AP–HP,75020Paris,France c

Departmentofgynaecologyandobstetrics,gyne´pole,AMU,Aix-Marseilleuniversite´,UM63,CNRS7278,IRD198,Inserm1095,Assistancepublique– HoˆpitauxdeMarseille,13005Marseille,France

d

LaboratoiresIPRADPHARMA,174,quaideJemmapes,75010Paris,France e

Universite´ Clermont-Auvergne,UMRMEDIS,CHUdeClermont-Ferrand,63000Clermont-Ferrand,France

Bacterialvaginosis (BV) is a common infectionestimated to affect approximately30% of women worldwide [1]. Prevalence variesfromregiontoregionwithalowerprevalenceinEurope– 24% in Norway and 19% in Poland [2]–but as high as 68% in Mozambique[2]andexceeding30%inSouthEastAsia,Australia andNewZealand[2].

BVistheresultofavaginaldysbiosiswiththedisappearanceor rarefactionof theLactobacillus flora and thedevelopment of a polymicrobialfloracombiningpredominantlyanaerobicbacteria, Gardnerellavaginalis(G.vaginalis),and/ormycoplasmas[3].Itis therefore not an infection per se but rather a multifactorial

imbalanceinthevaginalmicrobiota.Riskfactorsinclude:anew sexualpartner,a highnumber ofsexualpartners [4,5](maleor female[6]),smoking[4–7],vaginaldouches[8],andcontraception using an intrauterine device [9]. BVis a known risk factor for prematurebirths[10,11],chorioamnionitisandneonatalinfection, includinginbabiesbornatterm[11].BVisalsoariskfactorforHIV infection(relative risk=1.6)[12].Finally, BVrecurrence hasan impactonthepatient’squalityoflife[13].

ThediagnosisofBVisbasedontheclinicalcriteriadefinedby Amselin 1983[14].Womenarediagnosedas havingBVifthey present three of the following criteria: homogenous greyish leucorrhoea, rotten fish odour (spontaneous or following a potassiumhydroxidetest),avaginalpH>4.5,orthepresenceof clue cells by microscopic examination. Clinicaldiagnosis canbe confirmedbymicrobiologywithaNugentscoreof>7.Treatment

ARTICLE INFO

Articlehistory: Received7April2017

Receivedinrevisedform9November2017 Accepted22November2017

Availableonline28November2017

Keywords: Bacterialvaginosis Vaginalprobiotic Lactobacilluscrispatus Vaginalinfection

Recurrencebacterialvaginosis Metronidazole

ABSTRACT

Background. – Bacterialvaginosis(BV)isarecurrentdiseaseinwomendespitetreatmentbyantibiotics. Thisstudyinvestigatedtheimpactofavaginalprobiotic,LactobacilluscrispatusIP174178*(Lc),onthe rateofrecurrenceandtimetorecurrence.

Methods.– Aprospective,multi-centre,doubleblind,randomisedphaseIIItrialinwomenwithatleast twodocumentedepisodesofBVinthepreviousyear(diagnosisconfirmedbypresenceofthreeAmsel criteriaandaNugentscore7),andwhohadbeenclinicallycured(i.e.,noAmselcriteria)afteroral metronidazoletreatment(1g/day7days).Thepatientswererandomisedtoreceivevaginalcapsules ofeitherLcorplacebo,onceaday,for14daysoverthefirsttwomenstrualcyclesandanother14daysof thesametreatmentforthefollowingtwomenstrualcycles.Theprimaryefficacyendpointwasthe numberofpatientswithatleastonebacteriologicallyconfirmedrecurrenceofBV.

Results. –Outof98assessablepatients(meanage35.7years),78womenwereevaluated(20patients hadmissingdata).Duringthetreatmentperiod,16/39patients(41%)hadatleastonerecurrenceinthe placebogroupversus8/39patients(20.5%)intheLcgroup(P=0.0497).Thetimetorecurrencewas longerby28%intheLcgroup(3.750.16months)vs.theplacebogroup(2.930.18months)(P=0.0298). Tolerabilityandsafetyweregoodinbothgroups.

Conclusion. –InwomenwithrecurrentBVafterantibiotics,treatmentwithLcIP174178administered overfourmenstrualcycles,couldsignificantlyreducetherateofrecurrenceandincreasethetimeto recurrence.

C 2017PublishedbyElsevierMassonSAS.

* Correspondingauthor.

E-mailaddress:g.brami@iprad.com(G.Brami).

Available

online

at

ScienceDirect

www.sciencedirect.com

https://doi.org/10.1016/j.jogoh.2017.11.005

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forBVconsistsoforallyadministeredmetronidazole atadoseof 2500mgperdayfor7days[15,16].Theimmediateclinicalresults demonstratearecoveryrateof70%to80%[14],butarecurrencerate of33%at3months[17]andof49to66%at1year[18].

There are microbiologicalfactors associated with the recur-renceofBV:G.vaginalisandAtopobiumvaginae,twoofthemain bacteriainvolvedinBV,produceabiofilmthatadheresfirmlyto the vaginal wall [19] and which replaces the physiological lactobacillusbiofilm.TheG.vaginalisbiofilmhasbeenshownto beresistanttoantibiotictreatmentssuchasmetronidazole[20].

Several clinical studies[21–23] have shown that courses of probiotics (Lactobacillus rhamnosus, L. fermentum, L. plantarum, L. salivarius, L. brevis, etc.) reduce the symptoms of BV. Other studies [24,25] have explored Lactobacillus supplementation (L.gasseri, L.rhamnosus, L.acidophilus)in the preventionofBV recurrence.However, no studieshaveinvestigatedtheuseofL. crispatus, despite its beneficial properties. L. crispatus, and in particulartheL.crispatusstrainIP174178,isconsideredtobea biomarkerforvaginalhealth[3].Itproduceslacticacid, microbi-cideandvirucide,whichfacilitatetheexfoliationofglycogen-rich cells inthe vaginalepithelium [3]. Theaimof ourprospective, randomised,double-blind,superiorityclinicalstudy(Evaflore)was tostudytheefficacyandsafetyofL.crispatusIP174178 adminis-teredvaginallyinthepreventionofBVrecurrence.

Materialsandmethods

The study was carried out by gynaecologists and general practitioners in 29 centres in France between April 2013 and October2015.ItwascoordinatedbytheInstitutFournier(Paris). Studyprocedure

Selectionvisit(Visit1)

Patientshadtobeover18yearsandpresentwithallthreeofthe followingAmsel(Fig.1):

 homogeneousgreyishleucorrhoea;

 ‘‘rottenfish’’odourorpositivepotassiumhydroxidetest;  vaginalpH>4.5.

PatientshadtohavetwodocumentedepisodesofBV(medical recordsand/or bacteriological examination) within the previous year.AbacteriologicalsamplewastakentoconfirmBVandtorule outasexuallytransmittedinfection.Allpatientssignedaninformed consentformandwerecoveredbytheFrenchsocialsecuritysystem. Theexclusioncriteria weregenitalinfections,pregnancyand breastfeeding.

All patients meeting the inclusion criteria were prescribed metronidazole500mgtobetakenorallytwiceadayfor7days. Inclusionvisit(Visit2,Day0)

After completingthetreatmentwithmetronidazole,patients withaNugentscore>7atVisit1andclinicallycuredatVisit2(i.e., noAmselcriteria)wererandomisedtoreceivevaginalcapsulesofa

placebo or of L. crispatus IP 174178 (109 CFU per gram). The

treatmentconsistedofdailyadministrationofavaginalcapsulefor 14daysfortwomenstrualcycles.Thepatientswerecontactedby telephoneonDay28toensuretreatmentcompliance.

Follow-upvisit(Visit3,Day56)

Allthepatientswereclinicallyexamined. IfthethreeAmsel criteriawerepresent,abacteriologicalsamplewastakenandthe patientwasprescribedanewcourseofmetronidazole.

Compliance,adverseevents(AE)andconcomitanttreatments wereevaluated.

Another 14-day course of the same treatment (placebo or L.crispatusIP174178)wasthengiventoallthepatientsforthe nexttwomenstrualcycles.

ThepatientswerecontactedbytelephoneonDay84toensure treatmentcompliance.

Endoftreatmentvisit(Visit4,Day112)

All the womenwereclinically examined for the presenceorabsence ofthethreeAmselcriteriaandabacteriologicalsamplewastaken.

Compliance,AEsandconcomitanttreatmentswereevaluated. Endofstudyvisit(Visit5,Day196)

The women were clinically examined and a bacteriological samplewastakenasforVisit4.

Recurrencevisits

Ifvaginalsymptomsreappearedduringthecourseofthestudy and outside the scheduled visits, patients were invited to a consultation for a clinical examination and a bacteriological samplewastaken.

Objectives Primaryobjective

ToassesstheefficacyofL.crispatusIP174178intheprevention of BV recurrence by comparing the percentage of patients presentingwithaclinicalrecurrenceofBVconfirmedbyaNugent scoreof7attheendoftreatment(Visit4,Day112).

Theprimaryendpointwasthenumberofpatientsinthetwo treatment groups presenting with at least a bacteriologically confirmedclinicalrecurrenceofBVatVisit4(Day112).

Secondaryobjectives

 Time to first recurrence of clinical BV and clinically and bacteriologically confirmed BV between Visit 2 (Day 0) and Visit4(Day112).

 Numberofpatientspresentingwithatleastaclinicalrecurrence betweenVisit2(Day0)andVisit4(Day112).

 Numberofpatientspresentingwithatleastaclinicalrecurrence, numberofpatientswithatleastabacteriologicallyconfirmed clinicalrecurrenceandtimetorecurrencebetweenVisit4(Day 112)andVisit5(Day196).

 AEsatVisit5andoverallsafetyatVisit4(Day112).  Compliance.

Fig.1.Studyplan.

J.M.Bohbotetal./JGynecolObstetHumReprod47(2018)81–86 82

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Additionalanalyses

Average number of recurrences perpatient between Visit 2 (Day0)andVisit5(Day196).

Statisticalmethod

Theinitialsamplesizecalculationwascarriedoutonthebasis ofatwo-sided(

a

=0.05,

b

=0.20)

x

2(Chi2)testwithapowerof

80%and adifference inBVrecurrence of20% betweenthetwo groups. The percentage of patients without recurrence in the placebogroupwassetat50%.

Taking into account patients lost to follow-up (10%), 348patientshadtobeselectedtoinclude98assessablepatients in each treatment group giving a total Intent-to-treat (ITT) populationof196patients.

TheanalyseswererunusingtheSAS1

softwareversion9.3. We usedthe

x

2

test,tocompare thepercentageof patients betweenthetwotreatment groupswhopresentedwithatleast oneclinicalandbacteriologicalrecurrenceatVisit4(Day112).

We used theKaplan Meier methodto estimatethetime to clinicalrecurrence(regardlessofbacteriologicalconfirmation)and compared the time to clinical recurrence between the two treatment groups using the log-rank test (PROC LIFETEST) in unilateral expression. Patients lost tofollow-up were censored fromthisanalyse.

AEswerecodedusingthe2014editionoftheWHODrugDictionary. Thetwotreatmentgroupswerecomparedusingthe

x

2

test. We used the Wilcoxon rank test to compare overall safety betweenthetwogroupsatVisit4(Day112).

Boththe

x

2

testandtheStudentt-testwereusedtocompare compliance.

Randomisation was stratified by site and treatments were allocatedbytwoblocks.

Results

Studypopulation

Anydeviationswerereviewedandclassifiedasmajororminor duringadatareviewmeeting(Fig.2).

Safetypopulation(SAF)

Safety analyses was based on the safety population which included all randomised patients who had taken at least one treatmentcapsule(n=98).

Fullanalysisset(FAS)

TheFAS includedallrandomised patientswho had takenat least onetreatment capsule (n=98). Any randomisationerrors wereprocessedduringtheblinddatareview.

Perprotocol(PP)population

ThePPpopulationincludedallassessablepatientsintheFAS whofinishedthestudywithoutanydeviationfromtheprotocol (n=85).

TheefficacyanalyseswerecarriedoutinboththeFASandPP populations.

Demographicdataatinclusion

Themeanageof thewomenincludedwas35.7years. There wereno significantdifferencesinpercentagesbetweenthetwo treatmentgroupsregardingsmoking,useofanintrauterinedevice oruseofvaginaldouches.

Primaryobjectives

Outofthe98patientsintheFAS,ninepatientsintheplacebo groupand11patientsintheL.crispatusIP174178groupcouldnot beanalysedduetomissingdata.

In the FAS population, 16 of the 39 patients (41%) in the placebo group presented with at least one recurrence of BV [90% CI 28.1–54] versus eight of the 39 patients (20.5%) in the L. crispatus IP 174178 group [90% CI 9.9–31.1] (P=0.0497).

Outof 85patients inthePPpopulation,fourpatients inthe placebogroupandfivepatientsintheL.crispatusIP174178group couldnotbeanalysedduetomissingdata.InthePPpopulation, 16ofthe37patients(43.2%)intheplacebogrouppresentedwithat leastonerecurrenceofBV[90%CI29.8–56.6]versuseightofthe 39patients(20.5%)intheL.crispatusIP174178group[90%CI9.9– 31.1](P=0.0331)(Table1).

Secondaryobjectives

TimetofirstclinicalandbacteriologicalrecurrencebetweenVisit2 (Day0)andVisit4(Day112)

IntheFASpopulation(n=98),thetimetofirstrecurrencewas shorterintheplacebogroup,withamedianof2.930.17months comparedto3.750.16monthsintheL.crispatusIP174178group (P(log-rank)=0.0298)(Fig.3).

TimetofirstclinicalrecurrencebetweenVisit2(Day0)andVisit4 (Day112)

IntheFASpopulation(n=98),thetimetofirstrecurrencewas 2.840.17monthsintheplacebogroupversus3.760.17months intheL.crispatusIP174178group(P(log-rank)=0.0149).

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Numberofpatientsexperiencingatleastoneclinicalrecurrence betweenVisit2(Day0)andV4(Day112)

In theFAS population (n=98), more patients had a clinical recurrenceintheplacebogroup:47.5%(19/40patients,8patients notassessableduetomissingdataforthiscriterion)versus25% (10/40patients,10patientsnotassessableforthiscriterion)inthe L.crispatusIP174178group(P=0.0363).

Post-treatmentperiodVisit4(Day112)toVisit5(Day196) IntheFASpopulation,thepercentageofpatientswhopresented withaclinicallyand bacteriologicallyconfirmedrecurrence was 12.9%,withnosignificantdifferencebetweenthetwotreatment groups(P=0.9221).Likewise,nodifferencewasobservedintimeto firstrecurrenceofBVbetweenVisit4andVisit5:2.160.09months intheplacebogroupversus2.730.08monthsintheL.crispatusIP 174178group(P=0.8149).

Therewasnodifferencebetweenthegroupsinthenumberof patientswhohadaclinicalrecurrenceandtimetorecurrence.

InthePPpopulation,nodifferencewasobservedbetweenthe twotreatmentgroupsforthesamecriterialistedabove.

AdditionalanalysesbetweenVisit2(Day0)toVisit5(Day196) The average number of bacteriologically confirmed clinical recurrences, per patient, was lower in the L. crispatus IP 174178 group (0.30.7) versus the placebo group (0.70.9), withoutreachingsignificance(P=0.0779).

Safetyandtolerability

IntheFASpopulation,66.3%ofthepatientspresentedwithat leastoneAdverseEvent:70.8%intheplacebogroup(n=34)versus 62%intheL.crispatusIP174178group(n=31)(P=0.3550).

Threeof98patients(3.06%)presentedwithanAEconsideredto belinkedtothetreatment:twointheplacebogroup(vulvovaginal pruritis and leucorrhoea) and one in the L. crispatus IP 174178group(oralconsumptionoftreatment).

Five patients (two in theplacebo group and three in the L. crispatus IP174178group)discontinuedtreatment duetoanAE:twofor metrorrhagia(one in each treatment group), one for diarrhoea (L.crispatusIP174178group)andtwoforgenitalmycosis(onein eachtreatmentgroup).NoseriousAEswereobservedinL.crispatus IP174178groupwhereas2wereobservedinplacebogroup.

AtVisit4(Day112),overall tolerabilitywasassessedby the investigators as being: very good, good, average or poor. The tolerabilitywasdeemedtobeverygoodin92.2%ofcases,withno differencebetweenthetwotreatmentgroups(P=0.6061).

Compliance

Theaveragenumberoftreatmentdayswas53.911.7daysand theaveragenumberofdaysoftreatmentinterruptionwas5.77.2, with a median of 3.0 days, and no difference between the two treatmentgroups(P=0.3075andP=0.6128,respectively). Discussion

Our resultsshow that L. crispatus IP174178 (Physioflor1

) is effectiveinpreventingtherecurrenceofBV:59%ofthepatientsin theplacebogrouphadnorecurrenceattheendofthetreatment periodversus 79.5% ofthe patients in theL.crispatus groupIP 174178(Table1).

Sobel etal. [17]treated womensufferingfromrecurrentBV witheithertwoapplicationsperweekofametronidazolevaginal gelor with a placebo vaginal gel for 4 months.Following this treatment, 59% of the patients in the placebo group had no recurrenceversus75%ofthepatientsinthemetronidazolegroup. Theseresultsarecomparablewithours.However,prolongeduseof

antibioticcoursesintroducesnumerousdisadvantages,including theriskofresistance.

It is also interesting to note in our results that the first bacteriologically confirmed recurrence of BV occurred around 1 month later in the L. crispatus IP 174178 groupthan in the placebogroup(Fig.3).Likewise,theoverallanalysisoftheaverage numberofrecurrencesperpatient,uptoVisit5,showedabenefit of treatment with probiotics without reaching significance (P=0.0779). Thislack of significance maybe explained by the lackofstudystrengthduetooursmallsampleof58(29patientsin eachgroup)assessablepatients(forthiscriterion).

Thesafetyprofilewasgoodinthetwogroupswithonlyminor AEs.Twocases ofvulvovaginal mycosis,one ineach treatment group,werereportedwhichislowerthanotherstudies[24].

OurresultsalsoconfirmtheinvitrostudiesbyMcLeanN.W. andRosensteinI.J.[26],whichshowedthatL.crispatus55730 inhi-bitedpathogenicvaginalbacteria,andbyAtassietal.[27]showing that L.crispatus (108CFU/ml)inhibited G.vaginalisorPrevotella biviainco-culturefor4hours.

Somelimitationsneedtobetakenintoaccount:

 We were unable to meet our recruitment objective as our inclusioncriteriaweretooselective.Thewomenwererequired tohaveatleasttwobacteriologicallyconfirmedepisodesofBV withinthepreviousyear,whichhadtohavebeendocumentedin their medical records. The choiceto include patients witha demonstrated history of BVwasto ensurethat werecruited patients more likely to suffer a recurrence and therefore to betterevaluatetheimpactofthetreatment.Thiscriterionwas alsoappliedinSobeletal.’sstudy[17]andwasn’tintheLarsson etal.’sstudy[24].

Recruitmentstoppedafter167patientswereselectedinorder toremainwithinareasonabletimeframeforthestudyestimated tobecompatiblewithaninformativestatisticalanalysis.Despite thisreductioninsamplesize,theprimaryefficacyendpointwas positive. However, this might explain why we failed to reach significanceforfewsecondaryendpoints.

 Itispossiblethatthelengthofthetherapy(4months)andfollow up(3months)areresponsiblefortheamountofmissingdataat theendoftrial.AtVisit4,78patientswereevaluableforthe primary objective whereas at Visit 5, less patients were evaluable (number depending on the criterion), with a FAS populationn=98.Thelackofstatisticalpowerduetothissmall population couldexplain thenon-significance offew criteria evaluatedduringthefollowup.

 BVdiagnosiswasbasedonthepresenceofonlythreeofthefour clinical criteria defined by Amsel [14]. The fourth clinical criterion,whichinvolvestestingforcluecells,wasexcludedas mostoftheinvestigatorsdidnothavethenecessaryequipment available for this type of examination. Nevertheless, the presenceofthreecriteriaoutoffourrepresentsgooddiagnostic reliability, with a sensitivity of 70% to 92% [28,29] and a specificity of 94% to 99% [28,29]. Moreover, systematic bacteriological confirmation of BV using the Nugent score reinforced the diagnosis and limited the risk of wrongful inclusion.

 Whentheprotocolwaswrittenin2012,fewclinicalstudies investigating probiotics in the prevention of BV had been published. Furthermore,ourstudywas designedforwomen withahistoryofatleasttwodocumentedrecurrencesinthe pastyear.WebasedourstudydesignonLarssonetal.’sstudy

[24] which used a 10-day probiotic treatment schedule overfourmenstrualcyclesandin womenwho didnothave history of recurrences. Theseelements supportedour study

J.M.Bohbotetal./JGynecolObstetHumReprod47(2018)81–86 84

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applicationandthe scientificboardapprovedthe treatment periodof14daysforfourcyclesinwomenwithahistoryofBV recurrence.

 CertainBVriskfactors,suchassmokingandtheuseofvaginal douches,wereonlyassessedatinclusionandnotthroughoutthe studyandthismayhavecontributedtothefactthatwewere unabletodemonstratedlong-termefficacyoftreatment(i.e.,at Visit5).Likewise,datarelatedtothepatients’sexuality,whichis alsoaknownriskfactorofBVrecurrence,werenotcollected[5– 7].Theseriskfactorsmayhaveresultedinvaginaldysbiosisonce theprobiotictreatmentwasstopped.

 Duringthestudy,somewomenusedunauthorisedantibiotics whichcouldinducedysbiosis.Thesepatients weremonitored butnosignificantdifferencebetweenthetwotreatmentgroups wasidentified.Furthermore,thenumberofpatientswithatleast onerecurrencewasnotsignificantlydifferentbetweenthetwo treatmentgroups.

The2010CochranereviewbySenok[30]concludedthatthere wasinsufficientevidencetorecommend,ornot,probioticstotreat BV. But the authors did state that the Metronidazole with a probioticregimenappearedpromising:microbiologicalcurewas 88%intheMetronidazoleandprobioticgroupversus40%inthe Metronidazolegroupalone:OddsRatio0.09(95%CI0.03–0.25).It isimportanttonotethatthesestudiesarerelatedtothetreatment ofBVandnottothepreventionofBVrecurrenceasinourstudy. Otherstudies[24],[25]inthepreventionofBVrecurrencesupport metronidazole combined with probiotics over metronidazole alone.

Conclusion

Despitethelimitationsofthisstudy,ourresultssupportthat repeatedcoursesofvaginallyadministeredL.crispatusIP174178 (Physioflor1

)iseffectiveinthepreventionofBVrecurrence,witha timeto firstrecurrence significantlylater in theinvestigational group,withagoodsafetyprofile.Ourresultsarecomparablewith thoseobtainedwithprolongedcoursesofantibioticswithmuch

fewerenvironmentalrisksortheriskofresistance[20].However, theimprovementobtainedbyusingprobiotics,mustbeconsidered alongsidetheknownriskfactorsofBVinordertosustaina long-termbenefit.

Ethicalstatement

Thestudy(EUDRACTno.:2012-002975-33)wasapprovedby theEthicsCommitteeIˆle-de-FranceIIIandbytheFrenchHealth Authorities (Agence Nationale de Se´curite´ du Medicament (ANSM)). The study was carried out in accordance with the current ICH-GCP recommendations,the Declaration of Helsinki andFrenchregulationsandlaws.

Funding

ThisworkwassupportedbythecompanyIPRADPHARMA. Disclosureofinterest

DrBohbotwasPrincipalInvestigatorandscientificcommittee’s memberofthestudy,sponsoredbyIPRADPHARMADrDaraı¨,Dr BretelleandDrCardotwerescientificcommittee’smembersofthe study,sponsoredbyIPRADPHARMADrBramiandMsDanielare employeesofthecompanyIPRADPHARMA.

Acknowledgments

We would liketothankall thosewho wereinvolved inthe writing and review of this paperas wellas theclinicians who participatedinthestudy.

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Table1

Numberofpatientshavingatleastone(clinicalandbacteriological)recurrenceofBVbetweenV2andV4.

ClinicalandbacteriologicalrecurrencebetweenV2andV4 FAS(n=98) PP(n=85) Placebo (n=48) Lactobacilluscrispatus (n=50) Placebo (n=41) Lactobacilluscrispatus (n=44) No,n(%) 23(59.0) 31(79.5) 21(56.8) 31(79.5) Yes,n(%) 16(41.0) 8(20.5) 16(43.2) 8(20.5) 90%CI [28.1;54.0] [9.9;31.1] [29.8;56.6] [9.9;31.1] Total,n(%) 39(81.3) 39(78) 37(90.2) 39(88.6) Missing,n(%) 9(18.8) 11(22.0) 4(9.8) 5(11.4) (Chi2P)=0.0497 (Chi2P)=0.0331

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J.M.Bohbotetal./JGynecolObstetHumReprod47(2018)81–86 86

Figure

Fig. 1. Study plan.
Fig. 2. Flow chart.
Fig. 3. Time the first clinical and bacteriological recurrence (between V2 and V4)–Kaplan-Meier plot–FAS (N = 98).

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