ACROSTART: A retrospective study of the time to achieve hormonal control with lanreotide Autogel treatment in Spanish patients with acromegaly

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www.elsevier.es/endo

Endocrinología, Diabetes y Nutrición

ORIGINAL ARTICLE

ACROSTART: A retrospective study of the time to achieve hormonal control with lanreotide Autogel treatment in Spanish patients with acromegaly

Cristina Álvarez-Escolá

^a^,∗

, Eva María Venegas-Moreno

^b

, Juan Antonio García-Arnés

^c

, Concepción Blanco-Carrera

^d

, Mónica Marazuela-Azpiroz

^e

, María Ángeles Gálvez-Moreno

^f

,

Edelmiro Menéndez-Torre

^g

, Javier Aller-Pardo

^h

, Isabel Salinas-Vert

ⁱ

,

Eugenia Resmini

^j^,^k

, Elena María Torres-Vela

^l

, María Ángeles Gonzalo-Redondo

^m

, Ricardo Vílchez-Joya

ⁿ

, María Paz de Miguel-Novoa

^o

,

Irene Halperín-Rabinovich

^p

, Concepción Páramo-Fernández

^q

,

Guillermo de la Cruz-Sugranyes

^r

, Aude Houchard

^s

, Antonio Miguel Picó-Alfonso

^t

, on behalf of the ACROSTART Study Group

^♦

aEndocrinologyandNutritionDepartment,HospitalUniversitarioLaPaz,Madrid,Spain

bEndocrinologyDepartment,HospitalUniversitarioVirgendelRocío,Sevilla,Spain

cEndocrinologyandNutritionService,HospitalRegionalUniversitariodeMálaga,Málaga,Spain

dEndocrinologyDepartment,HospitalUniversitarioPríncipedeAsturias,AlcaládeHenares,Madrid,Spain

eEndocrinologyDepartment,HospitalUniversitariodeLaPrincesa,UniversidadAutónomadeMadrid,InstitutoPrincesa,Madrid, Spain

fEndocrinologyService,HospitalUniversitarioReinaSofíadeCórdoba,Córdoba,Spain

gEndocrinologyandNutritionDepartment,HospitalUniversitarioCentraldeAsturias,Oviedo,Spain

hEndocrinologyDepartment,Neuroendocrinology&EndocrineOncologyUnit,HospitalUniversitarioPuertadeHierro, Majadahonda,Madrid,Spain

iEndocrinologyandNutritionDepartment,HospitalUniversitarioGermansTriasiPujol,Badalona,Barcelona,Spain

jHospitalSantPau,CentrodeInvestigaciónBiomédicaenReddeEnfermedadesRaras(CIBER-ER,Unidad747),IIB-SantPau, Barcelona,Spain

kUniversitatAutònomadeBarcelona,Barcelona,Spain

lEndocrinologyandNutrition,ComplejoHospitalarioUniversitario,Granada,Spain

mEndocrinologyandNutritionDepartment,FundaciónJiménezDíaz,Madrid,Spain

nEndocrinologyandNutritionService,HospitalUniversitarioVirgendelasNieves,Granada,Spain

oEndocrinologyDepartment,HospitalClínicoSanCarlos,UniversidadComplutensedeMadrid,Madrid,Spain

pEndocrinologyDepartment,HospitalClínic,UniversitatdeBarcelona,Barcelona,Spain

qEndocrinologyandNutritionDepartment,ComplejoHospitalarioXeral-CiesdeVigo,Vigo,Pontevedra,Spain

∗Correspondingauthor.

E-mailaddress:[email protected](C.Álvarez-Escolá).

♦ Studyinvestigatorsarealllistedasauthors.

https://doi.org/10.1016/j.endinu.2018.12.004

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rMedicalDepartment,IPSENPHARMAS.A.,L’HospitaletdeLlobregat,Barcelona,Spain

sStatisticsDepartment,IPSENPHARMA,Boulogne-Billancourt,France

tEndocrinologyDepartment,HospitalGeneralUniversitariodeAlicante-ISABIAL-FISABIO,Alicante,Spain

Received3July2018;accepted6December2018 Availableonline14February2019

KEYWORDS Acromegaly;

Lanreotide;

SomatulineAutogel;

Dosageregimens;

Growthhormone (GH);

Insulin-likegrowth factor(IGF-I)

Abstract

Objectives: TheACROSTARTstudywasintendedtodeterminethetimetoachievenormalization ofGHandIGF-Ilevelsinrespondingpatientswithacromegalyadministereddifferentdosage regimensoflanreotideAutogel(Somatuline^® Autogel^®).

Methods:FromMarch2013toOctober2013,clinicaldatafrom57patientsfrom17Spanishhos- pitalswithactiveacromegalytreatedwithlanreotidefor≥4monthswhoachievedhormonal control(GHlevels<2.5ng/mland/ornormalizedIGF-Ilevelsin≥2measurements)wereana- lyzed.Theprimaryobjectivewastodeterminethetimefromstartoflanreotidetreatmentto hormonalnormalization.

Results:Medianpatientagewas64years,21patientsweremale,39patientshadundergone surgery,and14patients hadreceivedradiotherapy. Medianhormonalvaluesatstartoflan- reotidetreatmentwere:GH,2.6ng/ml;IGF-I,1.6×ULN.Themostcommonstartingdoseof lanreotidewas120mg(29patients).Themaininitialregimenswere60mg/4weeks(n=13), 90mg/4weeks(n=6),120mg/4weeks(n=13),120mg/6weeks(n=6),and120mg/8 weeks (n=9). An initial treatment regimen with a long interval (≥6 weeks) was administered in 25 patients.Meandurationoflanreotidetreatmentwas68months (7---205).Mediantime to achievehormonalcontrolwas4.9months.Injectionsweremanagedwithouthealthcareassis- tancein13patients.Mediannumberofvisitstoendocrinologistsuntilhormonalcontrolwas achievedwas3.Fifty-onepatientswere‘‘satisﬁed’’/‘‘verysatisﬁed’’withtreatmentand49 patientsdidnotmissanydose.

Conclusions: Real-lifetreatmentwith lanreotideAutogel resultedinearlyhormonal control inresponding patients,with hightreatmentadherenceand satisfactiondespitedisparity in startingdosesanddosingintervals.

PALABRASCLAVE Acromegalia;

Lanreótida;

SomatulinaAutogel;

Patronesde dosiﬁcación;

Hormonadel crecimiento(GH);

Factorde crecimientodela insulina(IGF-I)

ACROSTART:Estudioretrospectivodelperíododetiempoparalograrelcontrol hormonalconlanreótidaAutogelenpacientesconacromegaliaenlaprácticaclínica espa˜nola

Resumen

Objetivos: El objetivo del estudio ACROSTART era determinar el período de tiempo para lograrlanormalizaciónhormonal(GHeIGF-I)enpacientesconacromegaliarespondedoresal tratamientoconsiderandolosregímenesdelanreótidaAutogel(Somatuline^®Autogel^®)utilizados enlaprácticaclínica.

Métodos: Desdemarzode2013hastaoctubrede2013,en17hospitalesespa˜nolesseanalizaron los datos clínicos de 57 pacientes con acromegalia activa tratados con lanreótida durante

≥4 mesesque lograron controlhormonal (niveles de GH <2,5ng/ml y/oIGF-I normalizado en≥2evaluaciones).Elobjetivoprincipalfuedeterminarelperíododetiempodesdeelinicio deltratamientoconlanreótidahastalanormalizaciónhormonal.

Resultados: Lamediana de edaddelospacientesfue64 a˜nos,21pacienteseran hombres, 39 pacienteshabíanrecibidocirugía, 14pacienteshabíanrecibidoradioterapia.Los valores hormonales medianosal inicio del tratamiento conlanreótida fueron GH:2,6ng/ml, IGF-I:

1,6×LSN.Ladosisinicialmásfrecuentedelanreótidafuede120mg(29pacientes).Losprin- cipalesregímenesinicialesfueron60mg/4semanas(n=13),90mg/4semanas(n=6),120mg/

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4semanas(n=13),120mg/6semanas(n=6),120mg/8semanas(n=9).Seadministróunrégi- mendeintervaloprolongado(≥6semanas)en25pacientes.Laduraciónmediadeltratamiento con lanreótidafuede 68 meses(7---205). Eltiempomedio hastalograr el controlhormonal fuede 4,9meses. Las inyecciones semanejaron sinasistencia médica en13 pacientes. La medianadelnúmerodevisitasalendocrinólogohastaelcontrolhormonalfue3.Cincuentay unpacientesestaban‘‘satisfechos’’/‘‘muysatisfechos’’coneltratamientoy49pacientesno olvidaronningunadosis.

Conclusiones:EltratamientoenlavidarealconlanreótidaAutogelcondujoauncontrolhor- monal tempranoen pacientesque respondieron, conuna alta adherencia al tratamiento y satisfacciónconeltratamiento,apesardeladisparidaddelasdosisinicialesylosintervalos dedosiﬁcación.

Introduction

Acromegaly is a rare chronic endocrine disease, cha- racterized by enhanced growth hormone (GH) secretion and elevated insulin-like growth factor-I (IGF-I) levels;

the most frequent cause of which is a benign pituitary adenoma.¹ Persistently high levels of GH and IGF-Icause signiﬁcantmortalityandmorbidity,mainlyduetocardiovas- cularandrespiratorycomplications.²Therefore,controlof GHandIGF-Isecretionisdecisiveinimprovingsurvival.³

Thecurrentgoalsofacromegalytreatmentaretoelim- inatethetumoror,ifnotpossible,toreduceorcontrolits growth,normalizationofGHandIGF-Ilevelsandprevention andadequate managementofcomorbidities.²Therapeutic management strategies include surgery, radiotherapy and medical treatment. Pharmacological therapy plays a key roleinmanagingpatientswithacromegalywhensurgeryor radiotherapyarenotanoption,andconsistsofsomatostatin analogs(SSAs),lanreotide,octreotide,andpasireotide,as well as dopamine agonists and GH receptor antagonists.

SSAs have become the pillarof acromegaly medicalther- apy in patients whoare unsuitable for, or refuse surgery, afterfailureofsurgicaltreatment,orasprimarytreatment inselectedcases.⁴

InitialrecommendeddosesoftheSSAlanreotideAutogel (Somatuline^®Autogel^®,IpsenPharma)are60,90and120mg administeredevery28days.Thelong-termsafetyandefﬁ- cacyoflanreotideAutogelinpatientswithacromegalyhas been analyzed in previous studies. In a large cohort of acromegalic patients, sustained control of GH and IGF-I levelswasobtainedwithlanreotideAutogel,withapprox- imately 50% of patients obtaining GH levels <2.5ng/ml and/ornormalized IGF-Ilevelsbyweek 16 oftreatment.⁵ Experienceinstudiesevaluatingtheuseoflanreotideindi- catedthat alonger dosageinterval couldbeusedin well controlled patients with similar efﬁcacy,^6---9 thus suggesting that extending the dosing interval to 42 and 56 days maybeacommontherapeutic strategy.The starting dose forlanreotideAutogelprescribedinSpainmaydifferfrom prescribingrecommendations.⁸

In view of the above, this study (ACROSTART) was proposedtodetermine thetimetoachievehormonalnor- malizationcontrolconsideringtheinitialdosesanddosage intervals of lanreotide Autogel commonly used in clinical practice.

Material and methods

Studydesign

ACROSTART was a multicenter, non-interventional, retrospective, post-authorization study performed in adult patients with active acromegaly conducted at 17 centers in Spain. The centerswho participatedin the study were experiencedinthemanagementofacromegaly. Responder patients whose acromegaly wasmanaged with lanreotide Autogel were sequentially proposed from 08 March to 31 October2013toparticipateinthestudy.Asthiswasanon- interventional study,the decision to prescribe lanreotide Autogel was made prior to and independently from the patient’s enrolment into the study and it was prescribed as routinely at each center. The dosing regimens to be administeredwereentirelyatthediscretionofthetreating physician.

Studyincludedadults(≥18years)withactiveacromegaly (GHlevels≥2.5ng/mland/or non-normalizedIGF-Ilevels) whohad been treated withlanreotide Autogel monother- apyforatleast4monthsandachievedGHlevels<2.5ng/ml and/or normalized IGF-I levels on at least two consecu- tive evaluations (responder patients). The measurements musthavebeendonewithatleasta4-monthintervalprior tothe study.Patientswhose clinicalrecordslacked information regarding the date and initial dose of lanreotide Autogel and the ﬁrst hormonal response available were excluded. Patients that did not achieve hormone control or achieved only partial hormonal control were excluded fromthestudy.The studyincluded bothpatientswhohad undergonepriorsurgeryorradiotherapyorwhoweretreat- mentnaive.Patientswhohadreceivedpriortreatmentwith another SSAor other acromegalydrugs were alsoallowed tobe included in thestudy. Allpatients providedwritten informedconsent.

Toguaranteetheretrospectiveandobservationalnature of the study, the information was collected retrospec- tively from the patient’s clinical history chart and no additional diagnostic or therapeutic interventions were performed. Approval was obtained from the appropriate regulatory bodies, prior to study initiation. This study adhered to all local regulatory requirements applicable to non-interventional studies. Before initiating the study, each investigator/institution had obtained written and

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dated approval/favorable opinion from the Independent Ethics Committee (IEC)/Institutional Review Board (IRB).

The studywasperformed in accordancewiththerequire- mentsexpressedintheDeclaration ofHelsinki, aswellas Spanish legislation concerning observational studies. This studywasfundedbyIpsenPharmaS.A.,Spain.

Assessments

The following data were collected frompatients’ clinical history, when available: sociodemographic and socio- familiar data, data on the diagnosis of acromegaly, data related to the treatment of acromegaly, changes in co- morbidities(diabetes,carpaltunnelsyndrome,sleepapnea andarterialhypertension)andconcomitantmedicationsfor arterialhypertension anddiabetes, datarelatedtotumor control.Datarelatedtopatientsatisfaction(atthetimethat thepatientprovidedinformedsignedconsent,theinvestiga- toraskedadirectquestiontothepatientaboutsatisfaction with3possibleanswers[Verysatisfied,satisfied,notatall satisfied])andadherencetotreatment(determinedbythe numberofomitteddoses andbypatients’continuationof the treatment at the end of the study), and clinical and economicaspects(useofhealthcareresources:endocrinol- ogistandnursesvisits,laboratoryandimagetesting,daysof absenteeism[daysofabsenteeismweredefinedasthetotal sumofvisitstodoctor,hospitalnurseor outpatientnurse.

Eachvisitwasconsideredasonedayofabsenteeism])until obtainingcontrolofthedisease.

The levelsofGHandIGF-Iwerenotedatthefollowing times:atdiagnosis,presurgically,aftersurgicaltreatment, startoftreatmentwithlanreotideAutogelandwhenthese levels were normalized during treatment with lanreotide Autogel.Asthisisaretrospective,non-interventionalstudy, hormonelevels weremeasured asper clinical practiceat eachcenter;themethodswerenotstandardizedacrossdif- ferentcenters. Inaddition, thefrequency of study visits, biochemicaltesting, andradiological evaluationaswellas themethodsusedweredeterminedbytheendocrinologist incharge.

Asthiswasanon-interventionalstudyinwhichlanreotide Autogelwastobeadministeredandmanagedwithinroutine medicalcare,adverseevent(AE)reportingfollowedregula- tionsrelatedtospontaneouscases.Investigatorswereasked toreportonlyrelatedAEs(nonseriousandserious)tothe safetydepartmentofthemanufactureroflanreotideAuto- gelifthishadnotbeenalreadydoneatthetimeofonsetof theAE,usingtheusualprocessforsuchreactions.

Objectives

Theprimaryobjectivewastodeterminethetimetoachieve hormonalcontrol(deﬁned asGHlevels<2.5ng/ml and/or normalizedIGF-Ionatleast2differentevaluations)considering the starting dose anddosage intervals oflanreotide Autogel.

Secondary objectives included collecting clinical data onpatientsaccordingtoinitialtreatmentregimen,includ- ing changes in co-morbidities, determining the ability of theself-injecteither bythepatientora relative,theuse of healthcare resources until obtaining hormonal control,

assessing the effectiveness of lanreotide Autogel in con- trollingtumorsize,evaluatingpatients’generalsatisfaction with lanreotide Autogel therapy, and assessing patients’

adherencetolanreotideAutogeltherapy.

Samplesize

The sample size calculation was basedon the number of patients that, when included in the study, would provide sufficientinformationtodeterminetheprimarystudyobjec- tive.Thelong-termsafetyandefficacyoflanreotideAutogel inpatientswithacromegalyhasbeen analyzedinprevious studies.Specifically,thestudybyMelmedetal.⁵inalarge cohortofunselectedpatientsshowedsustainedcontrolof GHandIGF-Ilevelswithlanreotide Autogel,withapprox- imately 50% of patients obtaining GH levels <2.5ng/ml and/ornormalizedIGF-Ilevelsinweek16oftreatmentwith thefollowingdoses:60,90,120mgevery28days.Thislevel of control wasalso observed with an injection frequency every8weeks.⁸Thus,thesamplesizewascalculatedsothat thegroupofpatientsincludedintheACROSTARTstudyper- mittedanestimationofanassumedstabilizationof50%of patientsat16weeks,withaprecisionof±0.14percentage units.Assuminga2-sidedalphariskof0.05 (typeIerror), andapercentageoflossduetoincompletedata,inconsis- tencies,etc. of no morethan 20%, a totalof 59 patients weretobeincluded.

Statisticalanalysis

The primary analysis set (PAS) consisted of all screened patients who had taken lanreotide Autogel for at least 4 months, with date of hormone normalization recorded and without major protocol deviations. The primary and secondaryobjectives analyseswere performedonthe PAS population.Theprimaryobjectivewasthetimetohormonal normalizationonatleast2differentevaluationsconsider- ingthecommonlyusedstartingdosesanddosageintervals oflanreotideAutogel.Hormonalcontrolwasconsideredto havebeenachievedatthesecondevaluationandthistime point was used for statistical analyses. The primary and secondaryendpointswerereportedusingdescriptivequan- titativesummarystatistics.Todeterminetheeffectiveness oflanreotideAutogelincontrollingtumorsize,descriptive statisticsoftumorvolumeandpercentagetumorshrinkage wereobtained,asfollows:

% tumor shrinkage (at the most recent evaluations during treatment with lanreotide Autogel with regards to the start of treatment)=[(Maximum tumor volume at the most recent evaluations during treatment with lanreotide Autogel−Maximum tumor volume at the start of treatment)/(Maximumtumorvolumeatthestart oftreatment)]*100.

Results

Patients

Sixty-twopatientswerescreenedfrom08Marchto31Octo- ber 2013. Five patients were excluded from the analysis

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Table1 Patientdemographicsanddiseasecharacteristics.

PAS N=57

60mg/4weeks n=13

90mg/4weeks n=6

120mg/4weeks n=13

120mg/6weeks n=6

120mg/8weeks n=9

Male,n(%) 21(36.8) 4(30.8) 1(16.7) 6(46.2) 3(50.0) 3(33.3)

Patientableto self-inject,n(%)

8(14.0) 2(15.4) 2(33.3) 2(15.4) 0 0

Injectionbyfamily member/relative, n(%)

5(8.8) 1(7.7) 0 1(7.7) 1(16.7) 0

Injectionby

healthcarestaff,n (%)

44(77.2) 10(76.9) 4(66.7) 10(76.9) 5(83.3) 9(100)

Medianage,years (range)

64(23---90) 67(27---83) 51.5(30---77) 57(32---88) 73(23---90) 70(37---83)

Mediantimesince diagnosisuntil studyentry, months(range)

103.5 (8.1---325.5)

100.7 (14.6---285.0)

103.7 (8.1---128.4)

129.9 (19.3---284.2)

170.1 (17.9---325.5)

120.8 (41.6---218.6)

Typeofadenoma,n(%)

Microadenoma 22(38.6) 8(61.5) 2(33.3) 6(46.2) 0 2(22.2)

Macroadenoma 35(61.4) 5(38.5) 4(66.7) 7(53.8) 6(100) 7(77.8)

Priortreatment,n(%)

Surgery 39(68.4) 8(61.5) 5(83.3) 7(53.8) 4(66.7) 7(77.8)

Radiotherapy 14(24.6) 2(15.4) 2(33.3) 6(46.2) 1(16.7) 1(11.1)

HormonalvaluesatstartoflanreotideAutogeltreatment GH,ng/ml,median

(range)

2.6 (0.2---48.2)

2.65 (0.2---20.5)

3.90 (3.2---48.2)

2.52 (1.1---37.5)

1.58 (0.5---3.7)

2.84 (0.9---8.0) IGF-I(×ULN),

median(range) 1.6 (1.0---4.4)

1.6 (1.1---3.2)

4.0 (1.1---4.4)

1.4 (1.0---3.4)

1.1 (1.0---1.9)

1.4 (1.0---2.2) Microadenoma≤10mm,macroadenoma>10mm.

PAS,primaryanalysisset;ULN,upperlimitofnormal.

becausetheyunderwentsurgery or receivedradiotherapy aftertheinitiationoftreatmentwithlanreotideAutogelbut beforeachievinghormonalcontrol.ThePASpopulationcon- sistedof57patientswithamedianageof64years(range 23---90)atstudyentryandamedian ageatdiagnosisof51 years(range13---77).Demographiccharacteristicsareshown inTable1.Atstudyentrytherewere5patients≥80years old (80 years n=1, diagnosed at 53 years with extrasel- lar macroadenoma; 83 years n=2, both diagnosed at 65 years,bothwithmicroadenoma;88 yearsn=1,diagnosed at 77 yearswithmicroadenoma; and90 years n=1, diag- nosedat72yearswithintrasellarmacroadenoma);4were females.

Most patients (68.4%) began treatment because they were not able to obtain adequate disease control with surgery. The median time since the last surgery to start treatmentwithlanreotideAutogelwas33.9months(range, 2.3---191.0months).Therewere5(12.8%)patientsthathad more than one surgery. Presurgery and post-surgery hormone data are found in Table 2. There were 14 patients (24.6%) that underwent radiotherapy. The median time since the last radiotherapy to start treatment with lan- reotideAutogelwas12.6months(range,3.3---147.6months).

There were 11 (19.3%) patients that underwent both surgeryand radiotherapy,28(49.1%) that underwentonly

surgery,3(5.3%)thatunderwentonlyradiotherapy,and15 (26.3%)patientsthathadneitherpriorsurgeryorradiother- apy.

Injectionswere managed without assistance of health- carestaffin22.8%ofthepatients,eitherwithself-injections or administrationby closerelatives. Atotalof 19 (33.3%) patients received pre-surgical treatment. The most fre- quentpre-surgicaltreatmentwaslanreotideby10(17.5%) patients,followedbyoctreotideby6(12.3%)patients,and cabergolineby3(5.3%)patients.

When treatment with lanreotide Autogel was started, 18 patients were receiving pharmacotherapy for acromegaly, 10 (17.5%) with SSAs (4 lanreotide SR, 4 octreotideLAR,and2octreotide),7(12.3%)withdopamine agonists, 1 (1.8%) with GH receptor antagonists. At initiation of treatment with lanreotide Autogel, median hormonalvalueswereGH:2.6ng/ml(range0.2---48.2)and IGF-I:1.6×ULN(range1.0---4.4);29patientshadGHlevels

≥2.5ng/ml (47 patients ≥1ng/ml) and all patients had non-normalizedIGF-Ilevels.

Concerningsigns andsymptomsof acromegaly at diagnosis, acral growth was the most frequent, reported by 51 (89.5%) patients, followed by headache in 35 (61.4%) patientsandarthralgiain27(47.4%)patients.Medianhor- monal values at start of lanreotide treatment were GH:

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Table2 HormonedatainthePASpopulation(N=57).

Atdiagnosis Following presurgical treatment

Aftersurgery Atstartof lanreotideAutogel treatment

Athormone control^b

GH(ng/ml),n^a 54 16 35 53 46

Median(range) 8.0(0.2---177.0) 2.0(0.2---63.3) 3.1(0.1---177.0) 2.6(0.2---48.2) 0.83(0.1---5.7)

IGF-I(×ULN),n^a 40 14 32 53 55

Median(range) 2.2(0.9---5.1) 1.4(0.7---5.2) 1.4(0.2---7.4) 1.6(1.0---4.4) 0.8(0.4---1.5) GH,growthhormone;IGF,insulingrowthfactor;PAS,primaryanalysisset;ULN,upperlimitofnormal.

a Numberofpatientswithavailableinformation.

b Hormonalnormalizationonatleast2differentevaluations.Hormonalcontrolwasconsideredtohavebeenachievedatthesecond evaluationandthistimepointwasusedforstatisticalanalyses.

2.6ng/ml (range 0.2---48.2) and IGF-I: 1.6×ULN (range 1.0---4.4).

Mean treatment duration with lanreotide Autogel was 68months(95%CI55---80).Attheendofthestudyperiod, 47(82.5%)patients continuedwithactivetreatment.Lan- reotideAutogel120mgwasthemostcommonstartingdose (29[51%]patients).An extendeddosing interval(6, 8and 12 weeks) at lanreotide Autogel initiation was reported in 25 (44%) patients included in the study. Five differ- entsubgroupswerefurtheranalyzedaccording tostarting dosage pattern: 60mg/4 weeks (n=13), 90mg/4 weeks (n=6), 120mg/4 weeks (n=13), 120mg/6 weeks (n=6), and120mg/8weeks(n=9).Otherdosagesincluded:90mg/

6weeks(n=4),90mg/8weeks(n=3),60mg/8weeks(n=2) and 120mg/12 weeks(n=1). Dueto thesmall numberof patients, these subgroups were not analyzed separately (TableS1).

Primaryendpoint

Themediantimetoreachhormonalcontrolwas4.9months (range 1.2---117.0), Fig. 1. The median time to reach hormonal normalization in the 120mg/6 weeks subgroup (n=6)was8.2months(range2.8---117.0), inthe120mg/4 weekssubgroup(n=13)was8.1months(range2.2---106.8), in the 60mg/4 weeks subgroup (n=13) was 5.0 months (range1.2---57.6),inthe120mg/8weekssubgroup(n=9)was 4.2months(range1.8---22.0),andinthe90mg/4weekssub- group (n=6) was3.4 months (range2.6---28.3). More than halfofthepatients(n=37,64.9%)achievedhormonalcon- trolinlessthan10months;however,therewere4patients thattookover3yearstoreachhormonalcontrol(TableS2).

The median time to reach hormonal control among the 47 patients whowere not receivingan SSAwhen starting treatmentwithlanreotideAutogelwassimilartotheoverall population(4months[range,1---107months]).

Median hormonal values when hormonal control was achieved were GH: 0.83ng/ml (range 0.1---5.7) and IGF- I: 0.8×ULN (range 0.4---1.5) (Table 2). The median GH and IGF-I values in each dosage subgroup were 0.80ng/ml (range 0.1---4.3) and 0.9xULN (range 0.4---1.5) in the 60mg/4 weeks subgroup, 0.50ng/ml (range 0.3---2.0) and 0.7×ULN (range 0.6---1.4) in the 90mg/4

weekssubgroup,1.25ng/ml(range0.2---5.7)and0.8×ULN (range0.4---1.0)inthe120mg/4weekssubgroup,1.93ng/ml (range 0.7---4.5) and 0.8×ULN (range 0.6---1.0) in the 120mg/6weekssubgroup,and 0.99ng/ml(range0.4---2.8) and0.8×ULN (range0.5---1.0)in the120mg/8weekssub- group.

Secondary endpoints

Useofhealthcareresources

Globally,fromthestartoftreatmentuntilhormonecontrol obtained,themediannumberofendocrinologistvisits was 3(range1---64),ofhospitalnursevisitswas1(range0---64), andoutpatientnursevisitswas1(range0---132).

Overall, the median number of laboratory tests per- formedwas2.5(range1---20)whilethe mediannumberof imagingtestswas1(range0---9).Themediannumberofdays ofabsenteeismoverallwas6.5(range2---151)daysuntilhor- mone control was obtained. For the different subgroups, themediannumberof daysofabsenteeismwas10 (range 3---151) in the 60mg/4 weeks subgroup, 8.5 (range 5---20) in the 90mg/4 weeks subgroup, 13 (range 3---146) in the 120mg/4weekssubgroup,9(range2---81)in the120mg/6 weekssubgroup,and6(range2---23)inthe120mg/8weeks subgroup.

Controlofco-morbidities

Hypertensionwasreportedin29(51%)patients,bothatthe start of lanreotide Autogel treatment and when hormone controlwasachieved(28patientshadarterialhypertension atbothtimepointsand1patientwasreportedwitharterial hypertensionatthestartoftreatment,butnotathormone controland1patientdidnothavearterialhypertensionat thestart of treatment, but didat hormone control). The dailydose ofmedication forhypertension wasmaintained in 17 (60.7%) patients, the active principle was changed for5(17.9%)patients,dailydosewasincreasedin2(7.1%) patients,medicationwasdiscontinuedin2(7.1%)patients, dailydose wasreducedin1(3.6%)patient,andtheactive principlewaschangedplusthedailydosewasincreasedin1

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10 9 8 7 6 5 4 3 2 1 0

PAS 60 mg/

4 wks

90 mg/

4 wks 3.4 (2.6, 28.3)

8.1 (2.2, 106.8)

8.2 (2.8, 117.0)

4.2 (1.8, 22.0) 5.0

(1.2, 57.6) 4.9

(1.2, 117.0)

n=57 n=13 n=6 n=13 n=6 n=9

120 mg/

4 wks

Starting dosage of lanreotide autogel

Months

120 mg/

6 wks

120 mg/

8 wks

Figure1 Mediantimetohormonalcontrol,months(range).The10patientswithotherstartingdosagesoflanreotideAutogel:

90mg/6weeks(n=4),90mg/8weeks(n=3),60mg/8weeks(n=2)and120mg/12weeks(n=1),havenotbeenanalyzedseparately duetothesmallnumberofpatientsineachsubgroup.PAS,primaryanalysisset.

(3.6%)patient.Informationonhypertensionmedicationwas missingin1patient.

At the start of treatment with lanreotide Autogel 11 (19.6%)patientshaddiabetes.Whenbiochemicalcontrolof acromegalywasachieved,16(28.1%)patientswerereported withdiabetesandhadamedianHbA1clevelof6.9%(range 5.5---8.1).Thedailydoseofdiabetesmedicationwasmain- tainedin7(50.0%)patients,increasedin3(21.4%)patients, andreduced2(14.3%)patients,ﬁnally,themedicationwas changedin2(14.3%)patients.Informationondiabetesmed- icationwasmissingin2patients.

Carpaltunnelsyndromewasreportedin5(8.8%)patients whenlanreotideAutogel treatment wasstarted andwhen hormonecontrolwasreached,itwaspresentin2patients (3.5%). Sleep apnea was reported at the start of treatment in 11 (19.3%) patients. When hormone control was reached,sleepapneawasreportedin12(21.1%)patients.

Tenpatientsofthepatientswithsleepapneareportedthis co-morbidityatbothtimepoints(startoftreatmentandat hormonecontrol). In 1 patient sleep apnea was reported atthestartoftreatment,butnotathormonecontrol.Two patientsdidnotreportsleepapneaatthestartoftreatment butdidathormonecontrol).

Tumorsize

Atdiagnosis,22(38.6%)ofpatientshadmicroadenomaand 35(61.4%)had macroadenoma(21withextrasellarexten- sionand 14 intrasellar).There were 19 patients thathad informationontumorvolumeatthebeginningoftreatment withlanreotideAutogel,themeanmaximumtumorvolume in these patients was 2010mm³ (standard deviation [SD]

7801mm³).Only12patientshadinformationontumorvol- umebothatthebeginningoflanreotideAutogelandatthe lastevaluation during treatment withlanreotide Autogel.

Themeanmaximumtumorvolumeinthese12patientswas 3182mm³(SD38186mm³)atthestartoftreatmentwithlan- reotideAutogeland was2218mm³ (SD 26616mm³)at the most recent evaluation during treatment with lanreotide Autogel.Inthese12patients,therewasameanpercentage oftumorreductionof46.7%(SD36.9%).

100 90 80 70 60 50 40 30 20 10 0

Not at all Satisfied Very

satisfied 7.3

n=4

41.8 n=23

50.9 n=28

Patients (%)

Figure2 PatientsatisfactionwithlanreotideAutogeltherapy (n=55).*

*Informationwasnotavailablefor2patients.

Satisfactionandadherence

Globally,51outof55(92.7%)patientsreferredtobesatis- fiedorverysatisfiedwiththelanreotideAutogeltreatment (Fig.2).Only4(7.3%)patientswerenotatallsatisfiedwith thetreatment:onepatientinthe90mg/4weekssubgroup, onepatientinthe120mg/4weekssubgroupand2patients inthe120mg/8weekssubgroup,respectively.Information on‘‘satisfaction’’wasnotavailablefor2patients.

Therewasgoodadherencetotherapy.Globally49(86.0%) patientsdeclarednottomissanydoseduringthereporting period.The dose omissionsin 8 patientswere asfollows:

1doseomitted(n=2),1or2dosesomitted(n=1),2doses omitted(n=3),5dosesomitted(n=1),notspeciﬁed(n=1).

When subgroups were analyzed, compliancetotreatment wasobservedin92.3% patientsinthe60mg/4 weekssubgroup,83.3%patientsinthe90mg/4weekssubgroup,84.6%

patientsinthe120mg/4weekssubgroup,66.7%patientsin the120mg/6weekssubgroupand77.8%forpatientsinthe 120mg/8weekssubgroup.

Discussion

Inareal-lifesetting,asanalyzedin theACROSTARTstudy, themediantimeelapsedbetweeninitiatingtreatmentwith lanreotide Autogel and achieving hormonal control was 4.9months.Real-lifetreatmentwithlanreotideAutogelled

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toafasthormonalcontrol,withahightreatmentadherence and treatment satisfaction, despite disparity of starting doses and interval dosing. Very limited data have been publishedconcerningthedosingofSSAsin routineclinical practice.^6,7,10,11

In the ACROSTART study, therewere 9 different start- ingdosingregimensin57patients,fromthemost(120mg/

4weeks)totheleast(60mg/8weeks)doseintensity,reﬂect- ingthedisparityoftreatmentregimensinclinicalpractice.

Theredidnotappeartobeaspeciﬁcpatternexplainingthe investigator’schoiceoftheinitialdoseanddosageinterval of lanreotide Autogel. Patients might have started lan- reotideAutogeltreatmentwithanextendeddosinginterval iftheywerepreviouslywellcontrolledwithoctreotideLAR 20mgevery4weeks(q4w)or30mgq4w.However,patients whobeganwithlowerdoses/prolongeddosingintervalsof lanreotide Autogelmight have hada shortermedian time to hormone control achievement and may reﬂect a post- surgicalpopulationwithlowerinitialIGF-Ilevelsorsmaller tumors.Additionalanalysesonpatientsthatstartedtreat- mentwithlanreotideAutogelwithanextendeddosedidnot revealany baseline characteristics that couldexplain the initialchoiceoftreatment.Gender,age,timesincediagno- sisandhormonalvaluesatstartoftreatmentweresimilar.

Therewereslightlymorepatientswithmacroadenomasin the groupof patients startingwith anextended dose 76%

comparedwith61%intheoverallpopulation.

SSAshaveawell-establishedproﬁleandpatientsdonot typically discontinue treatment due to AEs.¹² In patients with acromegaly, the approved starting dose for SSA therapywasdeterminedinpharmacokineticandpharmaco- dynamic studies. The initial dosage of lanreotide Autogel can be 60---120mg administered every 4 weeks followed by adjustment based on GH and/or IGF-I levels. Guide- linesrecommendincreasingtheSSAdoseinresponsetothe patient’sneedforadditionalsymptomcontrolordecreasing thedoseifthepatienthasshownsignsofimprovement.²The dose adjustments recommend maintaining90mg/4 weeks if GH >1 to ≤2.5ng/ml, IGF-I normal and clinical symptoms controlled; increasing the dose to 120mg/4 weeks if GH >2.5ng/ml, IGF-I elevated and/or clinical symptoms uncontrolled; reducingthe dose to60mgq4wif GH

≤1ng/ml, IGF-Inormal and clinical symptoms controlled;

and considering an extended dosing interval of 120mg/6 or 8 weeks if patients are controlled on 60---90mg q4w.

In the ACROSTART study, the main starting dosing regimens were 60mg/4 weeks and 120mg/4 weeks followed by120mg/8weeks.Basedonpublishedstudies,dosetitra- tionoflanreotideappearstoimproveitsefﬁcacyinpatients withacromegaly,withmanypatientsrequiringescalationto 120mg/4weeks.¹³

Using pharmacokinetic model-based simulations, there wassupportthatpharmacologicallyeffectivelevelsoflan- reotide can be maintained after extending the dosing interval for lanreotide Autogel beyond the standard 4- weekdosinginterval.¹⁴Studiesevaluatingalternativedosing schemes in patients with acromegaly that was well controlled, prolonging thetimeintervalfrom4 to6/8 weeks betweenlanreotideAutogelinjectionsdidnotleadtoloss ofefﬁcacy.^6,9,15,16

In the large international clinical trial, Lanreotide Extended Autogel Duration (LEAD), hormonal control was

achievedwithlanreotideAutogelgivenatadoseof120mg onthe extended dosing interval (the ﬁrst 24 weeks at a 6-weekdosingintervalwithafurther24weeksata6-or8- weekdosinginterval)inpatientswithacromegalywhowere wellcontrolledwithoctreotideLAR10or20mg/4weeksfor

≥6months.⁹Three quartersof thepatients (75.8%)main- tainedIGF-Icontrol48weeksafterswitchingtoanextended dosing interval. The use of alternative, extensive dosing regimens may improve adherence to treatment and over timecanreduce both directdrug costsand indirectcosts suchasburdenonhealthcareresources.⁹ Lanro-Studywas an observational, prospective study, that evaluated over 24monthsthedosageoflanreotideAutogel120mginrou- tineacromegalycareinPoland.⁷Patientswereeligiblefor thestudyeligibleiftheyweretreatedwithlanreotideAuto- gel 120mg in routine practice for at least threemonths.

Of the 132 patients analyzed, 69 patients (52%) received lanreotide Autogel120mg/4 weeksand 63 patients (48%) receivedlanreotideAutogel120mgat adosinginterval>4 weeks.The Somatuline Depotfor Acromegaly(SODA) was an observationalstudy investigating theuse of lanreotide Autogel/DepotinclinicalpracticeintheUS.¹¹Patientswere eligiblefor thestudyiftheyweretreatedwithlanreotide Autogel/Depot, both patients who were treatment naive andthoseswitchedfromotheragents.Ofthe166patients enrolledin the study,60mg was the starting dose for 27 (16%)patients,90mgfor94(57%)patients,and120mgfor 45 (27%) patients. Almost all patients received injections every4weeks,but onepatientreceived120mg every≥6 weeks.UnliketheACROSTARTstudy,notallpatientsinthe Lanro-StudyortheSODAstudyhadachievedhormonalcon- trol.IntheretrospectiveanalysisoftheGermanAcromegaly Register,ofpatientswithacromegalyinGermany,407ofthe 1344patients(30.3%)hadreceivedSSAs.¹⁰ Amongpatients controlled(normalizedIGF-I)bylanreotidedepotmonother- apy (n=27), the median lanreotide dose was 60 (range 50---120)mgevery4weeks.Overall,themainstartingdoses reportedintheACROSTARTstudyin Spainarecomparable towhathasbeenreportedinclinicalpracticeinPoland,the US, and Germany, despite disparity of starting doses and intervaldosing.

IntheACROSTARTstudy,bothpatientsatisfaction(93%) aswell asadherence (86%) were declared ashigh by the patient.Although, alimitation regardingthecollectionof the adherence data was that it was collected from the patients’ clinical history. In the ACROSTART study, 22.8%

of the patients managed injections without assistance of healthcarestaff, which is higher than has been reported in the real-life study in Poland (2.6%),⁷ but lower than the real-life study in the US (40.4% at enrollment and 37.9% at 12 months)¹¹; suggesting that in Spain there is ahigheropportunity forself-injection.Studies havefound anincreasedpreference for selfor partner injectionover receivingtheinjectionbyahealthcareprofessional.^17,18In theSODAstudy,injectionbyhealthcarestaffwasconsidered less convenient than self or partner injection.¹¹ Further- more,achievementof biochemicalcontrolafter1year of lanreotide treatment was signiﬁcantly greater in patients whoexclusivelywereabletohomeinject(patientorpart- neronly)comparedwithpatientswhoreceivedinjectionsby healthcareprofessionals.¹¹ Although it may simplyreﬂect thefact that patients whoarebetter controlledvisit the

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physician’sofﬁce less often; it is also possible that there wasahigheradherence amonghomeinjectors. Similaror superiortreatmentadherencewithhomeinjectionhasbeen reportedinothertherapeuticindicationsthatrequireinjec- tionsthatcanbeadministeredbyhealthcareprofessionals orhomeinjection.^19,20

Thereareseverallimitationsinthisstudy,includingits retrospectiveandobservationaldesign.Animportantbiasto thestudywastheinclusiononlyofpatientswhoresponded totreatment.Furthermore,the GHandIGF-Ivalueswere obtained from several centers, measured as per clinical practiceand hadnot been previously standardized across all centers. As a reﬂection of real-life practice, the fre- quencyofstudyvisits,biochemicaltesting,andradiological evaluationweredeterminedbyeachtreatingphysician.In addition,thedistributionofthesamplesizeintosubgroups hasnotpermittedtoextensivelyexplorespeciﬁcoutcomes accordingtoinitialdosingpattern.However,itisspeculative tosuggestthatprolongedintervalinjectionscouldincrease patientconvenienceby reducingthe numberofvisits and tests.Additionally, pretreatmentwithotherdrugs, includ- ingSSAs,mayhavehadanimpactontheprimaryoutcomes.

Nevertheless,the median timetoreachhormonalcontrol amongpatientswhowerenotreceivinganSSAwheniniti- atingtreatmentwithlanreotideAutogelwassimilartothe overallpopulation.

Inconclusion,real-lifetreatmentwithlanreotideAuto- gelledtoanearlyhormonalcontrolinresponderpatients, witha high treatment adherence and treatment satisfaction,despitedisparityofstartingdosesandintervaldosing and provides clinical evidence that extending the dosing intervalto42and56daysinclinicalpracticeispossible

Funding

ThisstudywasfundedbyIpsenPharmaS.A.,Spain.

Conﬂict of interest

CAEreceivedhonorariafromIPSEN, NovartisandPfizer as speakerfees,hasservedonanadvisoryboard,receivedlec- turefeesandsponsorshipfortravelandaccommodationin internationalscientific meetingsfromIPSEN, Novartis and Pfizer.

CBC received honoraria from IPSEN, Novartis, Pfizer, AstraZeneca,Lilly, and NovoNordiskasspeakerfees,and receivedsponsorshipfortravelandaccommodationininter- nationalscientificmeetingsfromIPSEN,NovartisandPfizer.

MMAhasreceivedhonorariaasspeakerfees,hasserved onadvisoryboard,receivedlecturefeesandsponsorshipfor travelandaccommodationininternationalscientiﬁcmeet- ingsfromIPSEN,NovartisandPﬁzer.

EMThasreceivedhonorariafromIPSENandNovartis as speakerfees.

JAP hasserved on an advisoryboard, received lecture feesandsponsorshipfortravelandaccommodationininter- nationalscientiﬁcmeetingsfromIPSEN,Novartis,andPﬁzer.

EMVM has participated in conferences, courses, and steeringcommitteesofclinicalstudiespromotedbyIPSEN, Novartis,andPﬁzer.

MAGRhasreceivedsponsorshipfromIPSENforattending medicalconferencesandmeetings.

MPdMN has received honoraria as speaker fees and received sponsorship for travel and accommodation in international scientiﬁc meetings/trainings from IPSEN, Novartis,andPﬁzer.

IHR has participated in conferences and courses orga- nized by Novartis, Pﬁzer, IPSEN, and has participated in studiessponsoredbyNovartis,Pﬁzer,andIPSEN.

GdlCSandAHareIPSENemployees.

EMVM,JAGA,MAGM,ISV,ER,CPF,AMPAdonothavecon- ﬂictsofinterest.

Acknowledgments

The authors thank Francesc Pérez, an Ipsen Pharma employee,forhishelpduringdatacollection.

MedicalwritingsupportwasprovidedbyAuroraO’Brate andfundedbyIpsenPharmaS.A.,Spain.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.endinu.

2018.12.004.

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