An Open—Label, Community-Based,
`12-Week Assessment of the Effectiveness
`and Safety of Monotherapy With
`Doxycycline 40 mg (30-m Immediate-
`Release and 10-mg Delaye -Release Beads)
`
`Gu'y'F.WdJsIH.MD.F'li3
`
`were clear or near clear by week 12, accortfng to
`lGA scores. Furthermore, approximately 75% of
`participants had CEA scores reflecting none or mild
`erythema alter 12 weeks. in the safety population
`of 1195 participants,
`treatment-related AEs were
`reported in 6. 796 of participants that were mainly
`mild or moderate in severity. Adverse events that
`occurred in more than 196 of the safety popula-
`tion inducted diarrhea (1.2%), nausea (1.396). and
`headache (1.096). The incidence of fungal and yeast
`infections was 0.496. The results oi’ the ORCA trial
`support the etfecliveness and safety of the 40-mg
`formulation 01' doxycycline in patients with papulo-
`pustular rosacea.
`
`Gulls. 201D:B6tsuppI 5{ln:?-15.
`
`Fiosacea is a common inflammatory disorder of
`the skin of middle-aged and older adults. A
`unique 40-mg formulation of doxycycllne (30-mg
`immediate-release and IO-mg delayed-release
`beads) developed for its anti-inflammatory proper-
`tles is the only US Food and Drug Administration-
`approved oral medication for the disorder: This
`report describes the results at the Graces‘ tor
`Rosacea: A Community-Based Assessment fORCA,I
`trial. a pnase 4 trial of the 40-mg formulation as
`monotherapy in adults with mild to severe p8ptJ'lO-
`pustular rosacea. A total of 1 197 participants were
`enrolled in the monotherapy arm of the 12-week
`operrlabel study at 271 comrnunity-based inves-
`tiaatlonal sites. The primary outcome measure
`was a change in the 5-point investigator global
`assessment tic-IA) score from baseline to end point
`(week 12]. Secondary outcome measures included
`change in the 5-point clinician erythema assess-
`ment lCEA) score from baseline to end point, IGA
`success. and adverse events (AE5). The mono-
`therapv per-protocol (PP) population was selected
`a prinri as the primary analysis population and safety
`asses.-unonts were performed on all participants
`who received at least 1 dose of the study drug. in
`the PP population ol 826 monotnerapy participants
`who completed the trial, approximately ?5% of
`participants with mild to severe resacea at baseline
`
`osacea is a chronic demulaosis cl‘ middle-god
`and older adults that afects appmxirnauv.-ly
`16 million indivithels in the United States. a
`prevalerlu that is Y 4-fold greater than
`pwnams‘' .”AfarnilyhIstol1r” uflhed1sease' isrqnttrd
`in appmximalehr 30% of patients!‘ Roancea is char-
`auarimd by dilation afbleocl vemels at" the central
`facearndismttecommotninpntienuwhoexperience
`fiequer|tfltuIi:|gotbhd1i:|g.5'l'heetk)logyofmncea
`isLn1known;hawvever,itisaeeociaaedwithfac!asIhat
`trigger the skin'sir|rnIeiInn:.|r|eresponse.‘ Rosacea is
`hi:t.o|ogicallyvchaactcri::edbyintIamn|ationaI'|tIvas-
`cular changes.’ Patient: with msacee have increased
`e)q)rmionefepidermalcatbeIicidins.°The:epeptides
`have been demonmated to have antiniclubial, dw-
`mntactic, and angiogenic acu'vities.°'“ It has been
`sumeatad that increased expression of oalhelicidin
`Wc'|Mi'_G1JT'B_CClHl
`!uI'CI.Li|\E86.P1[NEl£IEFl ZCIIO 7
`Cqyrifliclisminlbpuldlismtloflulmqbarmmmmd. &ed.u'tmsII'lhdIn|l'Io¢IInpIioruflu|punieslor|otIuFu:lat'II.
`
`Fru11Jela'su'|MatiaIlGcIma,PlI‘|K!d:.i"n.PaI'riag1va'n.
`1halufirdaIabednInrqu'twmln'hdb:Gdchnn|.Ii'n'naiu.
`LPDr.Wd)atar'au1a‘Nisclybol'I1lTIBl'bfl:i'I\m1@cI'.a'1d
`ap§ta'hrGddurrnljn'fla'ias.LP.u'r!aooI'\a.trit:u'|1l—
`
`
`
`Amneal 1037
`
`Amneal v. Supernus
`|PR2013-00368, 2013-00371 and
`|PR2013-00372
`
`

`
` m
`
`and its tnpsinike proieolvtic processing ermrme.
`stratunrcorrieurn tryplic ¢1'l£FmBlSCTE). aecetittal
`elerm:n!aintl:iepa!hoge5IesisoftlIedisease.Tl'iis
`l'lfiI)d'ICSi!
`is iqapalted by iinnlmoliistocheniml
`evidence of increased calhelicidin and SCTE in
`rosaoea—£'ecteddcin.lnannnrirIenIodel.nibcutane-
`ousi:jectiaiisn{SCT'EpruhcedoiIariecnascl’nngeI
`
`Inhirmans.‘
`DoxycyI:lineliaslJeensl'iowntohavebod'ranti-
`bacnzrial and arrti-irifey properties. Pro-
`iriflanimatory mediators moihlated by Iteuacyclinia
`include phospliolipase A1. endogenous nitric oxide,
`ll.-i5.a':dsetineptoIeaaesnidiasSCTE.“-"In
`adrlicion, the drug chwn-neguhtes mm-ix Inenllov
`‘
`activity, inhilsiis cliernolnxk and gran»-
`fannation, and acts as a scavenger no pmtecl
`cells against reactive oxygen apei:ies."‘" Oracea"
`isalow-dose-10«rrigcapsI.iIeoI'doxycycIinernorio-
`hydrate oorttaiiing 30-mg imnedhte-release and
`IO-rng delayed-release beads (lieieirrafter referred to
`as doxycycline 40 mg)?‘ Its fotmulation and plur-
`mocokinetic profile are unique in that plasma con-
`oerittatioriadono-treachIeveIsproi:lI.icingarii:ilJiocic
`activity that would encourage the development of
`resistant organisms."
`t elements
`Tetracyclirles have been i
`ol'roIacead'ierapyformored1an50years."'nie
`US Food and Drug Adminismiiion
`ved
`die 40-rug formulation of doiqcycline mm for
`die treatment ofinflarrunatory papules and pusmlea
`inadtiltsurith rosinoea."'l'l'ieapprIJvaIIrasl3asedon
`die resuhs of I randomized. rnulticenter. I6-week.
`placebo-controlled. phase 3 trials of pmicipantn
`Irilhromcea.“ AlihooglitI1edru4;hasbeenavail-
`ablelordecadesandlihisforrnulationforalirioat
`
`5reax:.tliereh:vebcenriophase4trialsofitsnse
`as Inonodierapy in routine clinical practice.15 This
`report describe the phase 4 Oracea fix llosaoea:
`A Community-Based Assesrnenl: (ORCA) trial.
`Irl1icl'iwas-desigriedtoevaluatetl'ieellectiveries
`andsafetyofdnxycyclioe-l0nI'ginalun;erusIcea
`population used 5 either Inonotherqw or add-on
`therapy. This
`report describes
`the (lOXVCY-
`dirie40n1gmonod1a:;wa'rntfdiis|argecomnI.rnity-
`
`Good Clinical Practice guidelines. US Food and
`Drug Achinistration Code of Federal Regulations.
`and local regulatory requirements. The protocol
`was approved by a central
`iristiuninlial review
`board or
`the investigator":
`local
`institutional
`review board. All participants were fully informed
`about the stud)‘ and provided written consent prior
`to participation.
`
`SIudyPopi.lation
`Aihltsl8yeasaridoIder\veIeeligiIie§:xrl'iesn.idy
`i.fd'ieyl'iadadiagriosiscfmi|dto2ve1epaptIIcpus-
`tulwrouaceawitlrlnotleratelnsevere perilesiunal
`errlliema. Candidates were enchrlerl if they were
`pregriamorplannirrgrnhemmepreginririiuixigdie
`snidyziisedauopicalorsyslsemicacnedierapvlie.
`rel.iIEIitH.isoI1'etir'ioirl)v0iIl1irI1mcIiI}isoftlIel1meo
`linevislhlnedrrqaicalornymetnicxltibioficswidiin
`iweeksoldielaaselirietisitzliadlaserorirmuiae
`pi.Ilsedlfl'ittIeemIrntswit:hin3mcmtl'tsol'lhe
`
`tlietiriieoitiietrialztrsedariinvestigatiniialdrtigor
`devicewitliin90d=ysofhmeline;nsodatopicalor
`"M-*:°'“;-:~;.“.°*:.,*r~m°:*=.:*~°a
`respective‘;
`ine visit
`'
`so:d7;hadakiiawnhypersereinviryn:tcoacu"-r-inclines:
`were receiving lreatlllelil: fix ccnoonilnnt conti-
`tionsandwernenoltoriaslabledoseofrriedieation
`foratlseast3nioriI:hs:orliil:IaIwcoridit:io|id1atIhe
`invescigatordeemednaplaeetlieputicipmtatriilr
`orinleiiere wid'irl'iestudI;ou1:come.Ckl'iercaises
`foreincllnioti includedkidney dinaae. ,
`
`bypamedtliednodeinnn.activesvpteniicfiirigaliI1fec—
`tion,vaainiilrminfeccim,oonciIrentdiaeases,or
`a-adreiieiyiclalotzkerdierqiyinwliichdoaiiigwasrlnt
`stahleorwasanticipatedtodunge.
`Participanr.swereir|sm.ictedtotakelcqisule
`ofdoxycyclirieillmgdlilyinlliemorningciian
`emptystomaclrfordiedtiratioriofdi-ell-weektrial.
`
`ETHGJS
`
`mavinIaerfeteIriihahaorptionoi'rhe:nidvniedi-
`cation (cg. akiminum, calcium. . iron)
`upl.ol.5laoI.iubeforeandtIpto3hoursafterthe
`snJdyniediurommlnvesngatorseva|uatede:l:epar-
`ticipantimsaceaseverityariderytliermat
`ine
`andatweeks 2,4,8. and I2 (study end).SevIeriryof
`rosacearrasass-essedona5-pointinvestiganorglobal
`assessment (lGA)scalelTiJle l}.Altl'IetiIned
`This 12-Ireek.open-label. Inultioenter. community-
`I:helGAarse5snent.d|einvesI:ig:toraIsod1xacter-
`hosed trial evalmred doxycycline 40 mg in par-
`izeddisease-auociatedei11:hemaona5-pointclini-
`
`
`nci.pan'' tswithmildtoseve:erosac.ea(pa.I'uc'ipants
`who otherwise would have been treated with
`cianentliemaassesstnent (CIA) scale (Table 2).
`Safety was asseued by the incifince of advert
`anltiliintic-dose doxycytline} with the drug admin-
`events (AE5) that were descriptively suinniarized
`istered as rnonotherapy. This study was conducted
`in accordance with the Dechration of Helsinki,
`widiincideiiceratestabiilatedusirigtliehdedical
`'Jla"I\M‘.{2-l..F|I'u-OCIII
`BD.J1'|5‘
`Orpyflilciiuflfllfl. |bpltd'll'upIlifiuI'InIqhoIqIIn&IuIII. IhId.oI'lIII'I%lIiIIoiliII|:IiwII&ip-IiIa'nIIdIInFI.l1hlI-.
`
`
`
`

`
`
`
`Tablet
`
`lnvestigatorelobalfimsmrientscale
`
`
`
`some
`
`oeannson
`
`euiueane
`
`Otdaarl
`
`Nosiwfiorsvrrdmaneserwt
`
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`
`1tneardear]
`
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`
`iemurusuumuaypapues
`
`Ztrricll
`
`Scmepqndesandpuslules
`
`3—‘lOpqu|esH1c|pushJea
`
`3(rnochnte)
`
`Modauiemn-rberotpapuesandpustutes
`
`t1-19papuesa-adpusues
`
`“sane?
`
`NtmermsDanI1esarIdI:ush1es.noduies
`
`z2lJnan-Jesarldptnhlariodles
`
`Dictionary for Regulatory Activities‘ system organ
`class and preferred tenn.
`
`T3192.
`
`EnrlPoints
`
`Tl1e[.I'imaryoutcntII:me;mrrewasthetl'IangeinlGA
`scorefmm baseliner.oen:lpoint(weel1Z). Seconi:I-
`ar'you1corr|en1eanrresincludedclnr1geinC‘.E.Ascore
`from baseline to end point, success, and safety. For
`purpmnda1dyses,mccesscarHbedefinedasthe
`‘on cfueannentresputdersatemlpointwith
`an GA scoteoffl (clear) or I (neat clear).
`
`ChioianErylharna
`msunetttscdo
`
`score
`
`Otncnel
`
`limldl
`
`Delhltlon
`
`Norncheaepreaenl
`
`Sidiftiinknesfi
`
`Qlrnoduntel
`
`Oeirrtorutheas
`
`3{sigiicantJ
`
`Marl-cederylhura
`
`Stnliuficd Andyais
`This study was not powered. A large number of
`investigators participated in the trial to obtain a
`substantial body of evidence regarding the effec-
`tiveness and safety ofcloxycycline ‘IO mg when used
`in normal dermatologic practice. As discontinu-
`ation rates in a large open-label trial were antici-
`pated to be relatively high compared with smaller
`controlled trials, the per-protocol (PP) population
`was selected a ptiori for all effectiveness analyses.
`The PP population consisted of all participants
`who completed the 12-week trial without major
`rnaximurn). Baseline 104% stores were compared
`protocol deviations. The safety population was
`with subsequent IGA scores using the Cochran-
`defined as all participants who received at least
`Mantel-Haenszel (CMH) test. Similarly, baseline
`I doseof the study drug. Discrete variables such as
`CEA scores were compared with subsequent CEA
`certain delnngraphics, AB, and categorical effec-
`tiveness were summarized by frequencies {number
`scores using the CMH test. The baseline dichoto-
`mized IGA scores were compared with subsequent
`and percentage). Continuous categorical effective-
`ness variables were sutrunarized by mean. median,
`visits using the CMH test. Significance for all
`standard deviation, number. and range (mininrurn.
`hypotheses testing. except normal distribution, was
`‘I'uW'r\l'.CUTlS.OU.l
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`
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`
`Fluyredaeas
`
`

`
`Tfib 3.
`
`at CI=.U5. For nonnl distribution testing, signifi-
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`
`PuticipanlDaInog'npIics
`[Per-Protocol Population)
`
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`Panlcflaam Diapoalllon
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`the trial without a
`
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`formulation was approved Iaucd an In-016-It-cck.
`tImIumi.nul.pI1uc3clinicuI trials.“ Pu-ticipunuin
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