Case 1:14-cv-01453-LPS Document 43-14 Filed 10/22/15 Page 1 of 74 PageID #: 984
`Case 1:14—cv—O1453—LPS Document 43-14 Filed 10/22/15 Page 1 of 74 Page|D #: 984
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`EXHIBIT 41
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`EXHIBIT 41
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`Case 1:14-cv-01453-LPS Document 43-14 Filed 10/22/15 Page 2 of 74 PageID #: 985
`Case 1:14—cv—O1453—LPS Document 43-14 Filed 10/22/15 Page 2 of 74 Page|D #: 985
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`Proposed Claim Amendment
`
`(Korean Patent Application No. 2004-7020819)
`
`1. (Currently amended) A pharmaceutical formulation for nasal or ocular administration,
`
`which
`
`comprises
`
`azelastine ‘elaleeideor
`
`"a
`
`jgharmaceutically acceptable
`
`"salt
`
`L‘
`
`_
`
`3. F_a_p
`
`_
`
`1
`
`3
`
`1
`
`_
`
`&mefie h%%E and fiuticasonea steroid; or a pharmaceutically acceptable
`
`saltrsolvateesters ei*—ph{;=sielegieaH3yLwtttnetie‘' nal»£le1=i«;ati¥e—thereof,——pre£erabl§;L-tn‘e
`
`2. A pharmaceutical
`
`formulation according to claim 1, wherein said
`
`azelastine is present as azelastine hydrochloride.
`
`laeelomethason<+e1L—a—pliarrnaeeutieal-ly~aeeeptabl<%este1'
`
`este+‘«tlaereef,—l9uelesonideeiaeyteleseiaiele7in—a11»y—el=;iral—Eo§+r1—e1Ln1éxttir&
`
`phaH+1aeenta'c—all§,J—aeeeptabl<%ester«wthereof;—£lntieaseneea-a—pharmaeeutieally—aeeeptable
`
`thereof, memetasene or a
`
`(Cancelled) *'e ' ' ', ''
`
`
`
` '' '
`
`
`
`3.
`
`
`
`
`
`
`
`4. (Cancelled) A—fer~muEatienaeeoreling§to~elai»1n%*>r\aLhereinJelaesteroi€l—is—beelemethaeene
`
`prepienate;—memetasonem—firroate,——memetasone—»-t3aroate=~+neneh~y€l1=ate;——l3l+1tieasone
`
`p+'opienate—er—tlatleaseneJ+aleeate:
`
`5. (Currently amended) A formulation according to anyet‘-claims 1-te—4, which contains
`
`the fluticasonestereid in an amount from al.-3eut—50 micrograms/ml to abeat—5 mg/ml of the
`
`formulation.
`
`6. (Currently amended) A formulation according to an~y—ef—claims 1—te—§, wherein the
`
`formulation has a particle size of less than alaeut«l0 um7p%faab .
`
`7. (Currently amended) A formulation according to any—ef—clain1s l—te—6, which is a
`
`suspension containing 0.0005 to 2% (weight/weight of the formulation) of azelastine or a
`
`
`
`pliai-niaceutically acceptable salt. me1'eo§' "
`
`aeeeptalalewsaltef-a;seEastine—, and from 0.5 to 1.5% (weightfweight of the formulation) of
`
`fluticasone or a oharmaceuticalljg acceptab'le"est_e_1' t'he1'eo_fsaid-steroid.
`
`8. (Currently amended) A formulation according to claim 7, which contains from 0.001 to
`
`1% (weight./weight of the formulation) of azelastine or a Q.harmaceutically acceptable.-salt
`
`
`
`0.5% to 1.5% (weight/weight of
`
`the
`
`formulation)
`
`stereieiof
`
`fluticasone or "a
`
`MED_DYM_00002250
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`

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`pharmaceutically accegtable ester thereof.
`
`9. (Currently amended) A formuiation according to any—ef~clain1s 1—te—8, which also
`
`contains a surfactant.
`
`10. A formulation according to claim 9, wherein the surfactant comprises a polysorbate or
`
`poloxamer surfactant.
`
`11. (Currently amended) A formulation according to claim 9 or 10, which contains from
`
`abeut~50 micrograms to abeutl milligram of surfactant per ml of the formulation.
`
`12. (Currently amended) A formulation according to any—ef—claims l—te—i-l, which also
`
`contains an isotonic agent.
`
`13. A formulation according to ciaim 12, wherein the isotonic agent comprises sodium
`
`chloride, saccharose, glucose, glycerine, sorbitoi or 1,2—p1'opylene glycol.
`
`14. (Currently amended) A formulation according to anyaaiiclaims 14943, which also
`
`contains at least one of a buffer, a preservative and a suspending or thickening agent.
`
`15. A formulation according to claim 14, wherein said preservative is selected from edetic
`
`acid and its alkali salts, lower alkyl p-hydroxybenzoates, chlorhexidine, phenyl mercury
`
`borate, or benzoic acid or a salt, a quaternaiy ammonium compound, or sorbic acid or a
`
`salt thereof.
`
`16. A formulation according to claim 14 or 15, wherein the suspending agent or
`
`thickening agent
`
`is selected from cellulose derivatives, gelatin, polyvinylpyrrolidone,
`
`tragacanth, ethoxose (water soluble binding and thickening agents on the basis of ethyl
`
`celluiose), alginic acid, polyvinyl alcohol, poiyacrylic acid, or pectin.
`
`17. (Currently amended) A formulation according to anjeeeficlaims 14,—l—S—er—lL6, wherein
`
`the buffer comprises a citric acid-citrate buffer.
`
`18. (Currently amended) A formulation according to any—ef—claims l4 ,
`
`wherein the bufier maintains the pH of the aqueous phase at from 3 to 7Tp
`
`abeuiaé-.5.
`
`19. (Currently amended) A formulation according to anyeficlaims 1—ta—l-8, which is an
`
`aqueous suspension or solution.
`
`20. A formulation according to claim 19, which is in the form of an aerosol, an ointment,
`
`eye drops, nasal drops, a nasal spray or an inhalation solution.
`
`21. A formulation according to claim 20, which is in the form of nasal drops or nasal
`
`spray.
`
`MED_DYM_00002251
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`

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`22. A formulation according to claim 20, which is in the form of an aerosol.
`
`23. A pressure packing having a dosage or metering valve, which contains a formulation
`
`according to claim 22.
`
`24. (Currently amended) A M—Dl~metered dose inhale;j__(MD_l)__which includes a pressure
`
`packing according to claim 23.
`
`25. (Cancelled) &%H£edafieMxee mee o—l— ame¢eHn—&‘
`
`
`
`
`
`'‘ 'en—pewdei—'.
`
`26.
`
`(Currently amended) A pharmaceutical product comprising (i) azelastine or "a
`
`
`
`pha1'maceuticaily "acceptable (salt thereo 'eazeia~st~in ‘ - '
`
`
`
`
`
`a%epmb gi aee£ provided in an
`
`aerosol formulation preferablyetogether with a propellant for metered
`
`dose inhaler (MIDI) delivery, and (ii) tluticasoiieaelerwsteeaestereid, or a pharmaceutically
`
`acceptable salt,—seLv-ate or gsiergpifieielegiemhefiuaefienaidefiyamethereofi provided in
`
`an aerosol formulation preferablayetogether with a propellant k—for MDI
`
`delivery, as a combined preparation for simultaneous, separate or sequential use in the
`
`treatment of conditions for which administration of one or more anti-histamine and/or one
`
`or more steroid is indicated.
`
`27. (Currently amended) An aerosol fonnulation prefeH~1blyL—st1itable-fo1' metered dose
`
`inhaler (MDI) delivery comprising (i) azelastine or a pharmaceutically acceptable salt
`thereof
`"
`'
`,
`'
`'
`' .,
`el—vate——er
`
`
`
` '' ' '' ‘ , and (ii) fl11ticasoneat~least~ene—s%e+‘ei€i, or a
`
`
`
`
`
`pharmaceutically acceptable L$g§ e+'—physielegieallywfeaet~ienal—derivatixze
`
`thereof, together with a propellant.
`
`28. (Cancelled)
`
`acceptable—&
`
` e &m=i11acet1tic-all-3=ae
`
`I F__p}.;.” I_;_.’1
`
`.Ffi.fl
`
`powde1',——as—a—eeml9ined—preparatien~—foi=sirnaltaneeusTsepamteei»seqeential—use—i+1—the
`
`treatment-otleenditiens—fei‘—wl1ie1Eeadministratier}el1eaeoi=-- more anti—his-taa}incLand#or—ene
`
`or more stem-)iel—is indie tried.-
`
`29.
`
`(Cancelled) A-n—insul5flatien—pewdeiefemiuilatien~eempriisiag—(i)—azelasti-ne;—ea>a
`
`pharmaeeutieallyeaeeeptable~salt7sol=+ate—e1>1aI=1ysielogically funetienal+ieiai+£at-i-ve-E-liereefi,
`
`MED_DYM_00002252
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`

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`anel—(ii)~—ate—J;east»~ene—s.tereid,—e1'»1'1—phaemaeeatieaily—aeeeptable—saltT—selvat<%oi=
`
`phfiiole &mm%eeNmw gem hmhm%tiéeab%%epmem
`
`
`
`
`
`ea1=H'ei—ei—e=ee'‘ ,
`
`ipie—n*‘rthei=e£e1+—
`
`30. (Cancelled) Ajaharmaeeatiealrpmduet«eomp14sing—(i9—a2eiastine;o1La—phae1+1aeeatieail§£
`
`aeee3—3%alale4sa-lt«thereet]—anei—(ii—)-at~4easeene—stereiei—se4eeteleLfrenrtl1e—greapeonsisting~of
`
`beelomethzisenerflafieaeeaeanometaseneandphz'>a:n}aeeutieali—3Laeeeptalalee~steHHhe~reet}
`
`w%embmedp epa t1 amamatmanm‘
`
`%ndfiiem%e%4Hemmi+imEn%fiomePm%ePme #eeenae&mme
`
`stereidisindieatedr
`
`31. (Currently amended) A pharmaceutical formulation comprising (i) azelastine or a
`
`
`
`pharmlaceuticallygu acceptable salt 't11e1*eof ‘ ' '
`
`
`
` and (ii)
`
`beelemethaeeeerfluticasone or aupharmaceuticailyg acceptable ester thereof,—memetaeene
`
`together with a pharmaceutically
`
`acceptable carrier or excipient therefor.
`
`32. (Cancelled) A nasa-lJmr%%mnp tk%hL%%pmmesflt
`
`mae %%%mmmn%%o ea em%+memems%e
`
`§c1reate,—an€La13l1arrHaeeetieall{yLaeeeptaieieea1=sie1LoiLe:%eipient—therefo1a—
`
`33.
`
`(Cancelled)
`
`1A—ph{}Pl%}aG6H'EiG‘&l—pP6éHet—C-91-1%}3EiSlHg—-aztélfi-Sf~iH%—l5i§‘E1i=8Gi31E!HEle—at1€1
`
`beelemethasene~ei~iprepionate;was%1~eeinbined«prepaeatien~fei=si1aaelta-r1eeusreeparate—er
`
`seqaaniaHeem+heHeaHneneo£eendi&ens$eHwfiehadmefisHatmwefimeeememem%
`
`histanaine-and/oHane+9zL+nere4etereid—is-indéeated.—
`
`34. (Cancelled) A—phai=maeeutieal—fern+ela%ien—een1prising—a7zelastine—hydi>eehle14de—ané
`
`beQemedmma%d$mpien%a4o
`
`exeipient therei:—'er.—
`
`35. A pharmaceutical product comprising azeiastine hydrochloride and fluticasone
`
`propionate, as a combined preparation for simultaneous, separate or sequential use in the
`
`treatment of conditions for which administration of one or more anti-histamine and/or one
`
`or more steroid is indicated.
`
`36. A pharmaceutical formulation comprising azelastine hydrochloride and fluticasone
`
`propionate, together with a pharmaceutically acceptable carrier or excipient therefor.
`
`37. A pharmaceutical product comprising azelastine hydrochloride and fluticasone
`
`MED_DYM_00002253
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`

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`valerate, as a combined preparation for simultaneous, separate or sequential use in the
`
`treatment of conditions for which administration of one or more anti-histamine and/or one
`
`or more steroid is indicated.
`
`33. A pharmaceutical formulation comprising azelastine hydrochloride and fluticasone
`
`Valerate, together with a pharmaceutically acceptable carrier or excipient therefor.
`
`39.
`
`(Cancelled) Amh%r}me%ti%%pméa&—wrnm% ehle&d%%d
`
`
`
`
`
`
`
`
`
`
`
`meanetaseme ' , em ' ' ,‘ ° '
`
`
`
`ase—in-$he '* ' " " ‘ ‘" ‘e
`
`
`
`
`
`40. (Cancelied) Arpharn}aeeatieal—feenaalatien—eemp1=ising—aaselast+i+1e—l=iydHaelaleriele;and
`
`
`
`l'.
`
`41.
`
`(Cancelled)
`
`mmnem% mem% mmnw$mmmmw% maw
`
`
`
`
`
`
`
`
`
`
`
`
`
`r-mere
`
`eFseaua%iaHmanethe—treaanen% ' ' ' ' ' ' ' ' ‘
`
`
`
`
`
`
`
`42. (Cancelled) A$immm% ehmfide4nd
`
`niemetasenafiireatamenehydeatertegetheHa4th4i—pharmaeeatieallyeeeeptableearsie1eer
`
`e§eipient»the+efer.=~
`
`43. (Cancelled) Arpl=rarrnaee+itieal—t‘ermalaEien—s+rbstanEially—as—l3eRein—éeserib<%l~in—any—ef
`
`m
`
`44. (Currently amended) A process of preparing a pharmaceutical product according to
`
`any of claims 26, 28, 39,—33,—35,,— or 37, 3—9—er—4+,—which process comprises providing (i)
`
`
`
`
`
` azelastine or a ' harrnaceuticail acce "table salt thereof
`
`and (ii) fluticasoneat—least—ene—stereid, or a pharmaceutically acceptable salt7—sel—vateesters
`
`e ne% the1'eo£ as
`
`a combined preparation for
`
`simultaneous, separate or sequential use in the treatment of conditions for which
`
`administration of one or more anti- histamine and!or one or more steroid is indicated.
`
`45. (Currently amended) A process of preparing a pharmaceutical formulation according
`
`
`to any ofclaimsl 5 to 10 121 to l5 16 17 to 22, 27, 2.19, 31, 32£>4»;—36,-— or 38, 4&,42
`
`er—4~3,—which process comprises admixing a pharmaceutically acceptable carrier or
`
`MED_DYM_00002254
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`

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`Case 1:14-cv-01453-LPS Document 43-14 Filed 10/22/15 Page 7 of 74 PageID #: 990
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`excipient with
`
`azelastine
`
`or
`
`a
`
`gharmaceuticallyg
`
`acceptable
`
`salt
`
`thereof
`
`mflam and flL1ticaso11eat—1east—e-n<,Ls%eve'+d, or a pharmaceuticaily
`
`acceptabie ‘S‘31t","S9l‘VLa¥e er=ph§vLsielegic—al-¥)!—Ft:aePienal—eieei¥a!ei1sLe—the1‘eo£
`
`’_
`
`5
`
`,
`
`1’.
`
`,:....‘
`
`..
`
`,.
`
`‘
`
`g
`
`..
`
`_ fi%
`
`
`
`
`
`'' __ _m - tm mdue§e£
`
`.
`
`.
`
`_
`
`efme
`
`I
`
`_
`
`' Snag"...
`
`.
`
`.
`
`__
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`
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`MED_DYM_00002255
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`Case 1:14-cv-01453-LPS Document 43-14 Filed 10/22/15 Page 8 of 74 PageID #: 991
`Case 1:14—cv—O1453—LPS Document 43-14 Filed 10/22/15 Page 8 of 74 Page|D #: 991
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`EXHIBIT 42
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`EXHIBIT 42
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`Case 1:14-cv-01453-LPS Document 43-14 Filed 10/22/15 Page 9 of 74 PageID #: 992
`Case 1:14-cv-01453-LPS Document 43-14 Filed 10/22/15 Page 9 of 74 PagelD #: 992
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`“
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`Comparison of Intranasal Triamcinolone Acetonide with
`Oral Loratadine in the Treatment of Seasonal Ragweed-
`Induced Allergic Rhinitis
`
`Sandra M. Gawchik, DO; and [met Lirn, MD
`
`Abstract
`A double-blind, randomized, multicenter, paraliel-
`group controlled study compared the efficacy and
`safety of
`intranasal
`triamcinolone acetonide (220
`pg/day) and oral loratadine (10 mg/day) in patients
`with at least two seasons of ragweed-induced season-
`al allergic rhinitis. A 28-day screening period, includ-
`ing a 5-day baseline period, preceded a 4-week
`treatlnent period. Reduction in
`rhinitis
`symptom
`scores was evident in both groups as early as day 1,
`with no significant between-group differences during
`week 1. At weeks 2, 3, and 4, patients treated with
`triamcinolone acetonide were significantly (P < 0.05)
`more improved in total nasal score, nasal itch, nasal
`stuffiness, and sneezing than were patients treated
`with loratadine. At weeks 3 and 4, rhinorrhea and
`ocular symptoms were significantly (P < 0.05) more
`improved from baseline among triamcinolone ace-
`tonide patients compared with loratadine patients.
`There was no significant between-group difference in
`relief
`from postnasal drip at any time point.
`Physicians’ global evaluations significantly (P = 0.002)
`favored triamcinolone acetonide at
`the final visit,
`with moderate to complete
`relief of symptoms
`attained by 68% of triamcinolone acetonide patients
`and 59% of
`loratadine patients. Over the 4-week
`treatment period,
`triamcinolone acetonide patients
`had significantly greater improvement
`in total nasal
`score, nasal
`itch, nasal stuffiness, sneezing, and ocu-
`lar symptoms. Both treatments were well tolerated,
`with headache being the most frequently reported
`drug-related adverse effect in both the triamcinolone
`acetonide (15%) and loratadine (11%) groups. These
`results indicate that triamcinolone acetonide is more
`effective than oral
`loratadine in relieving the symp-
`toms of ragweed-induced seasonal allergic rhinitis.
`(Am 1 Man Care 1'997;3.-1052-1058)
`
`l’-‘rum Asthma and Allergy Assoiziatcs. Cm/.i:r-Cliester Mr-3r.li<:.r|
`(Icmcr. Cl1(‘.:5l(-SI‘, PA (S.M.(‘..), and Rlione-Poulent: Ron-:r l’lianuaci~uli-
`cals, lnc., (:Oll(.‘.g(‘.Vlllt?. P/\ (l.I..).
`Address tzorrt-spondence to: Sandra M. Gawchik, DO, Asthma and
`/\|li-my Assotzizalcs, Cm/,or-(Iliuster Medical Center, <;'ho.ster. PA 19013.
`This study was spon_~:ored and Sl.l|)[)()flt?(l by Rlifilie-l’ot)lenc Rorcr
`l"|1nrmact-‘uticals, Int‘.
`
`agwced pollen-induced seasonal allergic rhinitis
`
`R-aftects -an estimated 10% to 15% of the North
`
`American population.” It is it typical hypersen-
`sitivity response in which a susceptible individua|’s ini-
`tial exposure to antigen (ragweed pollen) stimulates the
`li)1'mz1ti0n of lglil antibodies. Subsequent. exposure to
`the same antigen 'd(.'l'.l\-’at;CS these antibodies, resi.ilt.ing in
`the dcgr-anulurion of mast cells and thc release of
`inflarnmatory mediators
`such as histaminc
`and
`leultotricnes. ll‘ is these mediators that cause the clini-
`cal symptoms associated with allergic rhinitis.
`(lltaractcristic-ally, the symptorn complex consists
`of pziroxysms of sneezing, nasal pruritus and obstruc-
`tion, clear
`rhinorrhca, and palatal
`itching. Ocular
`symptoms.
`including Conjunctival
`irritation and
`lzicrimat.ion. may also be present.‘ In some individuals.
`the immediate (early-pllasc) response is followed by 21
`recurrence of symptoms within 4 to 24 hours. The
`late-phase response, which appears mainly -as nasal
`obstruction. is usually more difficult to treat.
`The morbidity associated with seasomil allergic
`rhinitis is often sufficiently scvcrc to require therapy
`for relief of symptoms. If left untre-ated. these symp-
`toms lead to €.\'<lC(‘Il'l')'c1tl0n of more scrious conditions
`such as sinusitis, bronchitis, ascluna. or other r<:Spi1“at(‘)~
`ry discascs.
`lf practical.
`the susceptible individual
`should avoid or minimize exposure to the allcrgcn.
`It’ environmental control is not feasible. the tradi-
`tional mainstay of treatment of allergic rhinitis has
`been the antihisutmines, specifically H;-receptor
`antagonists.’ "l"lic classic first-generation ll,-rcceptor
`ztntugonists l1-ave :1 rapid onset of action. and they
`counteract.
`snc<:1.ing[,
`pruritus,
`and
`rhinorrhie-.1.
`I-lowevcr, their minimal cl"t'cct on nasal congestion and
`their primary side cfli-:cts of sedation and central ner-
`vous systcm impairment render them unacceptable to
`some patients. Second-gt-znerution l"ll-l'('.'(.'(.‘pU)l." antag-
`onists, which -act by l)lt)ckiiig l-I, receptors -and
`decreasing 1”.ll(.‘
`release ol” intlummatory mcdizt1‘.()rs
`responsible for the allergic symptoms, include l(Jftttzl-
`dine.
`tertcnadinc, and cetirizinc.
`'l"hesc untihistu~
`
`1052
`
`’I'I-~l]'i AMF.RI(.'.AN JOURNAL or MANr\(§l:'D emu:
`
`_]Ul.\.’ l‘)97
`
`
`
`MED_DYM_00002724
`
`

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`'l'RlAM(3lN()l.0Nl;' v1=.asus LORATADINI3 FOR RAGWHJD-INI)UCI$I) ALl.l;'RGl(; RHINITIS
`
`mines Cause less sedation and anticholinergic action
`but, like their predecessors. have little to no effe.ct on
`nasal congestion." One study found loratadine and ter-
`fenadine to be etguivalenr in providing symptomatic
`relief in allergic rhinitis."
`Other options available for treating symptoms of
`seasonal allergic rhinitis include decongestants (a-
`adrenoceptor agonists). cromolyn sodium (a mast. cell
`stabili'/.ing
`agent).
`topical
`corticosteroids,
`and
`immunotherapy.’ Currently. intranasal st.eroids (which
`include triamcinolone aeetonide. beelomethasone
`dipropionate. flunisolide, flutieasone propionate. and
`budesonidc) are the treatment of choice for allergic
`rhinitis. Various studies have compared the efficacy of
`nasal steroids with that of antihistamines in the treat-
`ment of allergic rhinitis.""" Intranasal steroids have
`been shown to control symptoms better than cromolyn
`sodium and second-generation antihistamines and
`tend to he as effective as immunotherapy.“ intranasal
`steroids inhibit both the early and late phases of aller-
`gie responses.”
`'l.'lris article provides the results of a comparison
`between intranasal
`triamcinolone acetonide 220 pg
`once daily and oral
`loratadine 10 mg once daily in
`patients suffering the symptoms of ragweed-induced
`seasonal allergic rhinitis.
`
`l’ATlEN'l'S AND METHODS
`
`V\=’e conducted a double-blind, randomized, multi-
`center. parallel-group study. Because both intranas-.rl
`steroids and second-generation I-1,-receptor antagonists
`have been shown to be effective allergy medications. we
`did not include a placebo arm."”"" 'T‘he study was divid-
`ed into a screening period oliup to 28 days, which includ-
`ed a baseline period (the last 5 days of the screening
`period). and a double-blind treatment period of 28 days.
`Patients were restricted from using any concomitant
`edications for rhinitis (eg, decongestants and antihist-
`amines) throughout the study.
`The study and its procedures were explained to
`prospective patients. and those enrolled signed an
`informed consent statement. A total of 305 male -.md
`female patients, aged 12 to 70 years, were enrolled in
`the study. All met the entry criteria for seasonal aller-
`gic rhinitis, defined as a medical history of at least two
`consecutive seasons of allergic rhinitis cl1aracteri7.ed
`by rhinorrhea, sneezing. nasal stuftiness, nasal
`itch.
`and postnasal drip, with or without ocular symptoms.
`The diagnosis was verified by a positive skin-prick
`allergen test response to ragweed.
`Patients testing positive to eat or dog allergens
`could not have these allergens in their present envi-
`
`ronmenr during the study period. Pregnant or lactating
`women, as well as women o{"chi|dl>earin_g potential not
`practicing an approved method of contraception dur-
`ing the study. were excluded.
`I"-atients who had
`received long-acting steroids or had used deconges-
`tants regularly within 3 months of the baseline period
`were not accepted; neither were patients who had ini-
`tiated immunothcrapy within the previous month or
`who were receiving medication that might cause. sup-
`press, or exacerbate the symptoms of seasonal allergic
`rhinitis. Also excluded from the study were habitual
`abusers of nasal decongestants. patients with a history
`of hypersensitivity or nonresponse to [()pi(I‘.ll steroids
`or antihistamines,
`-.md patients with sinusitis or any
`concomitant illness that could jeopardi'/.e the evalua-
`tion of the study medication.
`Post‘-admission exclusion criteria included the use
`of any additional medication that could relieve or
`cause rhinitis. any nonsteroidal medication deemed to
`interfere with the assessment of the study drug
`(including antihistamines, cromolyn sodium, and
`decongestants). and all steroids except oral contracep-
`tives and replacement therapies.
`
`Study Design and Procedures
`During the screening evaluation (visit 1). the fol-
`lowing procedures were performed for each patienr:
`medical history: physical examination: fasting clini-
`cal
`laboratory tests (including urinalysis, hematol-
`ogy, and serum chemistry); and skin tests consisting
`of extracts of ragweed. A/mvm/'1'a mold, dust mites,
`and cat.
`dog.
`and cockroach allergens. The
`skin-prick test to ragweed allergen had to result in a
`wheal (_>_ 3 mm) and flare (.>_ 10 mm) greater than the
`negative saline control. In addition, serum [2’—l'l(.'.'(_i
`pregnancy tests were done for women with repro-
`ductive potential.
`lV'.ach patient was given a diary in which to rate
`the severity of the following rhinitis symptoms each
`day: nasal stuffiness. rhinorrhea. postnasal drip, ocu-
`lar symptoms. sneezing, and nasal itch. The sum of
`all four nasal symptom ratings constituted the toral
`nasal score.
`
`Patients rated the severity of each of these primary
`variables according to the following scale:
`
`0 = None: symptoms absent
`1 == Mild: symptoms present but not annoying
`2 = Moderate: symptoms present and annoying
`3 = Severe: symptoms interfere with daily activities
`or sleep
`
`On concluding the last 5 days of screening‘ (the
`drug-free baseline period), patients who had satisfied
`
`V()].. 3, NO. 7
`
`'l'Hl'I AMI-IRl(.'.AN JOURN/ll. OF MANALSIED CARI?
`
`M r()5.i”
`
`
`
`MED_DYM_00002725
`
`

`
`Case 1:14-cv-01453-LPS Document 43-14 Filed 10/22/15 Page 11 of 74 PageID #: 994
`
`
`
`DISEASE MANAGEMENT
`
`the entry requirements and had at least 5 consecutive
`days of symptom scores recorded in their diaries
`returned to the center for baseline evaluation (visit 2.
`study day 1). Patients who had a combined total nasal
`score ofat: least 24- points during 4 of the 5 days of the
`baseline period qualified for the trial and were ran-
`domized into one of‘ the following treatment groups;
`
`Group 1: Triamcinolonc acctonidc nasal aerosol
`inhaler, S5 },(.g/spray,
`two sprays/nostril. and placebo
`capsule, both once daily
`two
`inhaler,
`Group 2: Placebo nasal aerosol
`sprays/nostril, and loratadine H) mg (the tablet placed
`within a capsule), both once daily
`
`Patients were instructed how to use the nasal
`
`inhaler. The first dose of study drug was administered
`under the direct supervision of the investigator.
`Daily pollen counts were obtained from each site.
`enabling all patients to start their study medication
`within 1 week from the time ragweed pollen was air-
`borne. Patients were instructed to take the medication
`
`in the morning, at least l hour before or 2 hours after a
`meal, and to record their symptoms and medication
`usage daily. Patients were scheduled to return for eval-
`uation after 2 and 4 weeks of" treatment (visits 3 and 4,
`respectively).
`At visit .3 (study day )4 .+_ 3 days), patients were
`given a limited physical c.\'amin-arion, and the physi-
`cian made a global evaluation of treatment effective-
`ness relative to the highest 4 of S symptomatic days of
`the drug—free baseline period. 'The following was used
`for these evaluations:
`
`0 = No relief
`
`1 = Slight relief
`2 = Moderate relief
`3 = Marked relief
`4 = Complete relief‘
`
`In addition. patient diaries were reviewed. a new
`supply of medication was administered with instruc-
`tions, and all case report form documentation was
`entered by the investigator.
`At visit 4 (final treatment evaluation, study day 28
`i 6 days) or whenever a patient terminated study par-
`ticipation, complete physical cxarninations,
`fasting
`clinical laboratory tests, and physician global evalua-
`tions were performed. In addition, patient diaries were
`collected and reviewed, all remaining study medica-'
`tion was returned to the investigator, and all case
`report form documentation (including adverse experi-
`ence, concurrent illness, and concomitant medication
`information) was completed. Upon completion of these
`procedures, the patients were released from the study.
`
`Efficacy and Safety Measures
`l:‘Zll'3c:1cy was evaluated for patients who satisfied the
`inclusion-exclusion criteria of the protocol and complied
`wir.h the study schedule and protocol requirements, who
`had continuous efficacy diary data for at least 7 days, and
`who received at least 85% of study medication. The pri-
`mary variables were assessed by Comparing the change
`from baseline in the. average daily rhinitis symptom
`scores. Tlic secondary variables were assessed by (I)
`p-.-rticnt dropout
`rate due to insul‘Frcient
`therapeutic
`effect. (2) physician global evaluations relative to the
`highest 4 our of 5 symptomatic days of the drug—t"ree
`baseline period, and (3) time oi.’ onset. of action for each
`of the first 7 days of treatment.
`Salety data were evaluated by observing changes in
`the eyes, nose, mouth, and throat (including infection
`and mucosal lesions); medical history; adverse events
`(all-treated and drug-related); changes in physical
`examination parameters; and changes in clinical labo-
`ratory measures. "l"hese data were evaluated for all
`patients who received at least one dose of study drug.
`
`Statistical Analysis
`Descriptive statistics were used to summari"/.e base-
`l.inc characteristics by treatment group. Tlie significance
`of a center by treatment interaction was investigated
`with a two-way analysis of variance model with center,
`treatment group, and treatment-by—center interaction
`effects at the level of 10% for the changes from baseline
`in mean total nasal score in all treated patients. The
`change from baseline data were investigated with a
`two-way analysis of variance model with terms for treat»
`ment group and center effects. A Wilcoxon sum of rank
`test stratified by center was used if the distributional
`properties of the data did not meet the assumptions for
`analysis of variance. A Cochran—MantcI-1-Iaenszel
`test
`stratified by center was used to compare the physician
`global
`evaluation and patient dropout
`rate. A
`Mantel~l-~laens'/.el chi-square test or l*‘ishcr’s exact test
`was used in case of data sparseness.
`"lo assess the impact of pollen count on the effica-
`cy comparisons. daily mean changes from baseline for
`total nasal score and for each rhinitis symptom score
`were plotted against pollen count using Z scores. cal-
`culated by the following formula:
`
`.1
`
`_ Actual Pollen Count - Overall Mean Pollen Counts
` ndardMl)eviatio'n of the Pollen"Counts
`
`For onset of action, 95% confidence intervals were
`plotted for each of the first 7 days of treatment by
`treatment group. Descriptive statistics were used to
`sumrnarize the following safety variables: changes
`
`'l‘l~lli .'\Ml3Rl(.'.t\N JOURNAL OF MAN/\(fil¥l') CARE
`
`JULY 1997
`
`
`
`MED_DYM_00002726
`
`

`
`Case 1:14-cv-01453-LPS Document 43-14 Filed 10/22/15 Page 12 of 74 PageID #: 995
`Case 1:14—cv—O1453—LPS Document 43-14 Filed 10/22/15 Page 12 of 74 Page|D #: 995
`
`
`
`1‘RlAM(Ill\’()L()Nli VERSUS LORA'l‘AI.)iN!3 FOR Rr\(iWliI§D-INDlJCIjD ALl.l§RGl() RiiiNi'i‘is
`
`from bzisclint: to final visit in \-"it-.11 sigii |')'<ll'2liT|CiI(‘.‘l'.S'
`and in iaborzitory parzimeters (zlctllzli and |'C'i2ll'i\’c;
`
`>:SlJI11.r¥.1£l.|'y of Pzilienl l.')<':riiog,i‘ap|ii(:s and
`Table 1.
`An‘-"Be" 5""5"'V”
`
`'~°"“3‘“"°
`E
`(" ’
`'53’
`32.0 _+.. 12.0 ’
`
`!
`:,
`i
`
`65 (439411
`
`1
`
`68 (50%;
`I38 (90%)
`I2
`i3‘Vi.i)
`ii"/0)
`((M0)
`74-2 1 19-7
`
`F(.‘Ih£l|(,‘
`'
`M-‘*"‘
`Ril(',(' or Ethnic Backgroiiiiij
`if Wliilv.
`‘
`a
`'3l_«i(~i<
`Hispiiimz
`; Am”
`ii Weight, Kg fiheaiii 1 SD!
`E
`History of allergiiz rliinili-5,
`37'5iH’2 !*
`‘(M ‘t 12")
`y('“°‘mi'S"»
`:
`W
`,
`_,_.
`,_
`3 ’\|3""'3"" S_‘:"""."""")'
`m.)0.':)
`1:
`:]3(2)0.,/;;))
`’'
`mom
`(41.24))
`3.
`._0
`.
`.
`g
`(,3 ((,4_,«-/,,,
`33
`(57_9%,
`i
`[)u5i ,,,;k._,,
`‘
`78 (5)23)
`72
`1,.-i7.-4%)
`" Cal
`-._
`44 (28.8%)
`37
`(2-i..'i%i
`Dog
`
`I
`39 (255%)
`26
`“7"°’;"
`C""k"""""‘
`
`
`
`_
`3
`3 V“""‘1"°
`i
`go.
`~,i (inc.-m .+. siiii
`i 5,,‘
`
`‘
`
`T'i3""'5""""K‘ A“"°"id*=
`(" ’ '52)
`33.7 1; i3.0
`
`0" 543"/0)
`
`mi (57%)
`I30 ((21%)
`9
`(6%)
`(<|“/n)
`1
`3
`(2%)
`73--1 .1. 19-7
`
`ranges), -adverse c:fi-bets reported by
`to norm-.1]
`iiivestigzimr, incidence of ])l'Cn'l2ll”lll'(.‘ diS(?0l1tiI1llil-
`tion of treatment, and siimmzirv of concomitant
`'“°di°"“i‘?““;
`,
`,
`I.)eseripti\'e statistics were also used to si_im~
`
`izrezitment of drug
`
`l‘n2ll'i'/.('.‘ mediea! histories and tot-ai dose, compli~
`and dlll'2lCi()n of
`2In(.'C,
`2'l(iIniniSU"dCi()i1.
`All statistical eoinparisons ofrre:ir.inent groiips
`were two—sided at a 95% Ievei oi'sigi1iFiez1iiet; (l’ <
`.
`_
`_
`0.05) unless otherwise Stzltcd.
`__..
`RESULTS
`trczited
`The baseline dl‘.‘l11(')_gl'2l])i1i(.'S for all
`patients were C()n1p2H'zlbiC for the two trezicmcnt
`groiips with respect to age. sex, rzice, weight, zind
`'__‘
`I_
`_ __
`__
`_
`h
`V
`ustory of zille.igi(. rhinitis ( Iaible 1). Pzitacnts l'¢ll1g<.‘-(.1
`.n age from 12 l'.() 68 years (lTl(:ill'l -= 33 .1 Y(':2l]'S). All
`152 patients in the tri-.imeinolone zieetonide group
`and 21” 153 patients in the lorzitzidine group tested
`positive for nigweed zillergy."'l"lie medical
`histories of p-.icients in both groups were
`similar.
`
`Oi" the 305 patients enrolled in the
`study, 140/152 (92%) pzitients in the tri-.im—
`cinolonc acctonicic group and 136/153
`(89%) patients in the Iorzitzidine group eom-
`pleted the study.
`Ifiiglit putiems in i;-cu,-h
`.
`“ea[mL.nL group Wue pr"mdn"c,]y With-
`dl‘2l\'-='11 from the study’ because 0!‘ adverse
`events. Four patients in the tri-.1m<.-inolone
`?“5C'5(mid‘-i g“ml-" and Six in Ch‘:
`]()"?‘C?1dm‘3
`group were WiChCil'2iV\-'n because 01’ pl'Ol”(.)C(.)i
`dcviatioiis or noneomplizinec or were lost: to
`i‘oJlow—iip. Three of the iorziczidinc putierits
`are diseontiniied due to izlck iifeffiezicy. A
`total of 279 wzitients
`I42 zinc! 137 res )(:C-
`1
`’
`1
`.
`u\:;_>_.[y) were evaluated fur c1'hcuCy_
`
`lifficacv
`The companitive effiscts ofrrizimeinolone
`_
`.
`_
`.
`.
`.
`.
`2l(.'(:[()l‘l1dC and loratadine on rhinitis symp-
`toms for each ofthc 4 weeks oftrezitment :-ire.
`_ n 1_ Wei
`. T bl_ 2 A” _l.
`.
`._
`_
`su iilflf ,. ( _in
`.i
`c 4.
`iiinitis symp-
`toms, incli.idim_r, ocular svmptoins, improved
`.
`I
`1
`___
`" _
`_'
`'
`_
`I
`_.
`:
`in )oti tI(:¢ll:1i1<;I1C gioups tuiing week 1-
`I he six rhinitis symptoms improved lrom
`__
`_
`.
`_‘
`(,1
`, ,0
`.
`_
`_._
`ni<..iii bil.S(.iln(. by 25 (
`to .361;
`in the tii
`ameinolone zieetonide _i,,»'i'i_iiip and by 22%
`1»
`I
`to 34% in the. i(.)l"all.';-ldillf.‘ _'l'()ll ); however,
`
`Table 2. Summary of P(:|'(‘.GI)l' Recluclions from Mean Baseline. in
`
`Allergy Symptoms
`
`ii
`2
`1
`‘I
`
`V
`
`1
`
`i
`
`L
`
`H
`
`M
`
`I
`
`W i
`
`ii
`
`Week 1
`
`W095‘ 2
`
`W'~‘0'< 3
`
`Wwk 4
`
`(‘I (
`
`i
`
`3|
`39
`
`.30
`34
`
`27
`'33
`
`‘.25
`27
`
`:”
`J]
`
`38
`32
`
`46'
`_g(,
`
`51‘
`41
`
`40°
`29
`.
`37
`33
`
`7"}
`36
`
`54”‘
`4]
`
`5-1'
`.10
`
`02‘
`-i7
`
`40*
`3‘
`
`44
`325
`
`5","
`-10
`
`63‘
`44
`
`7
`
`54‘
`43
`
`65'
`53
`
`48"
`3"’
`
`43
`40
`
`5 3 V
`40
`
`63*
`43
`
`E
`.,
`
`
`Ti'iam(.iiiol()iieaizetimide
`i_(,,ma,i,,,.,
`NM, M,‘
`Tri.ini<:iiio|on(-.-zicelonide
`'7
`Lamiaciine
`i
`I N,mi S|i_||'fin(§§§
`g
`'i'n'.imcinoione .‘iC(':t(.iiiid(,:
`i
`L""*'”-""“"‘-‘
`i P0.<.in.i:..iI If):-ii
`.
`i
`.
`.
`'
`E
`Ti'i.im< lll0|()I"lK‘ zimioiiide
`E
`Ltimieidino
`E Rliinorrhea
`E
`1""""°"_“"""“' ‘"‘‘"°"'d‘*
`'
`Lmaladiiie
`E
`,
`1 5"“_""'“§
`Tri.'ini(‘.ino|om-acelonide
`Lm,madm(_
`A
`.
`Ociilar Sympioms
`e
`57*
`59*
`47
`34
`Trizmiciiiolcine a(.'el0iii(J(-*-
`
`
`it
`4.;
`4;;
`33
`39
`L,,,,.i,,,iim..
`.
`,_._,,..,,.,.mW...,..
`mm...,,.,..,,.._..“.,._,.._.,W_._._t,._....,,,,,,.w.,...t,..,..........,.,n
`.,.,<0.05 wwsus |0l_mdiW_
`tp< Um ,,(,,,.,.u5 .,,.._.m,,;;.,¢._
`"P< 0.01 versus |0i'eil.!dii‘ie.
`
`VOL. 3, NO. 7
`
`THF. 1\Ml.’.Rl(','t\.N JOURNAI. O1: MANAGIED (LAKE
`
`105 5
`
`
`
`MED_DYM_00002727
`
`

`
`
`Case 1:14-cv-01453-LPS Document 43-14 Filed 10/22/15 Page 13 of 74 PageID #: 996
`Case 1:14—cv—O1453—LPS Document 43-14 Filed 10/22/15 Page 13 of 74 PagelD #: 996
`
`
`
`D