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`Case 1:14—cv—O1453—LPS Document 43-13 Filed 10/22/15 Page 1 of 69 Page|D #: 915
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`EXHIBIT 36
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`EXHIBIT 36
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`

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`Case 1:14-cv-01453-LPS Document 43-13 Filed 10/22/15 Page 2 of 69 PageID #: 916
`Case----1:l4—cv—O1453—LPS- ~- Document 43-13 - Filed 10/22/15 Page 2 of 69 Page|D-: '
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`CLlNiCAL TRIAL
`
`
`The New Topical Steroid Ciclesonide
`Is Effective in the Treatment
`
`of Allergic Rhinitis
`
`Bernhard M. W.’ Schmidt, MD, Wolfgang ’1'lmm_er, MD, Anette C. Georgens,
`Monika Hill, Catherine Mottinger, MD, Wilhelm Wurst, MD,
`Karl Héirmann, MD, andMa1'l1"n Wehling, MD
`
`
`
`
`
`' Jllnrandomized, placebo-controlled, d'oubIe—bllnd crossover
`study was performed to investigate the efiicocy of ciclesonfde
`nasal spray in allergic rlu'm‘tz's or the dose level of200 pg per
`nostril. Twenty-four subjects (13 males. 11 females: median
`age: 28 years} with a history of allergic rhinitis lmtl free of
`symptoms at-screening entered the study. Cfclesonide on_d'pIa—
`cebo were given for 7 days each with o washout period of at
`least 14 days in between. In both treaonentpefiods, controlled
`lntranasol allergen provocation with pollen extmcts waspor-
`formed on the 2 days before start oflrsotment {days -2 and-1)
`and on all i‘reatment.a'ays (days 1 to 7} about 2 hours after
`udministmtian afthe study medication. Al. 5 and 30 minutes
`
`after each allejgen provocation, n’u'nal airflow was measure
`by anterior rh1'n_oman_ometr_;r. and the subjective symptoms
`obstruction, itching, and rhinortrhea were assessed by mean
`of a stun dordized visual analog scale. Rlzinal airflo
`improved signaflcanflyfiom day 5, while the subjective sym
`tom of obstruction improved from day 2. ItcIu‘ng- and rhino
`rhea also improved significantly. The local and systemic.
`tolerobillty of ciclssonfde nasal spray was "excellent.
`'I?1e*‘
`results of this study clearlylndicatefhat the new topical sfe ‘
`old ciolesonlde is effective in the tre_at_msnt ofallergic rIu'mft
`._
`without producing local or systemic side effizcts.
`Journal of Clinical Plmrm ecology, 19s9}3s:1os2-1_os9'
`@1999 the American College of Clinical Pltarmacology;
`
`
`llergic rhinitis is-a common disease that is charac«
`terized by nasal obstruction, itching, 1*-hinorrhea,
`and eye symptoms. Allexgic rhinitis can occur season-
`ally and in a perennial form. Seasonal allergic rhinitis
`is triggered mainly by natural pollen exposure, while
`perennial allergic rhinitis may be caused by various
`environmental allergens. After exposure to a specific:
`antigemmediators such as prostaglandin D2, leukem-
`ene E4, trypiase, and histamine are released during an
`early allergic reaction, which causes sneezing, nasal
`
`From the.lll-sllihrle ol Clinical Pharmacology, Mannheim University Hospifpi,
`Rupreclat-‘Korfs-University HeidelberfifiMannheim,§Germofj§§(Dr. Schmicll,
`Ms. Georgens, Prof. Welding}; Byl<W'Gulden Phorrooceulicols, Konslonz.
`Germany (Dr. Tlmmer, Ms. Hill, Dr. Wursl]; and line Daparlmenl ol Clarifi-
`noloryngology, Mannheim University Hospital, Ruprecht-Korls~UniversEty
`Heidelberg, Mannheim, Germany (Dr. Maffinger, Prol. Hermann). Submit-
`ted forpubliccnlion December I 4. 1998; revised version occapied May 25,
`l999. Address lor reprints: Prof. Martin Wehling, Head all 1116 lnsiifufe ol
`Clinical Pharmacology, Mannheim Universily Hospital, Faculty of Clinical
`Medicine Mannheim, Ruprschr-Kurls-University Heidelberg. Theodor-
`Kulzer-Ufer 1-3, D-68 l 67 Mannheim, Germany.
`
`1052 0 {Clix} Pharmacol §999;3Q:1flB2-1069
`
`blockage, and rhinorrhea. After improvement of symp
`toms, a late-phase reaction may typically occur.
`
`between 3.5 and 8.5 hours after allergen provocation 1
`Allergic inflammation in the "nose is mainly due to;
`recruitment of eosinophils and metachromatic cells.”
`Human allergen-induced responses in the nose are j
`used as a suitable model for allergic inflammation.“
`Allergicrhinitis effects 8% to 24% of tllepopulation
`in the industrialized countries.“ In patients suffering
`from allergic rhinitis, the heaIth—:e1ated quality of life
`is frequently impai1'ed..Whe_n complete allergen avoid—
`mice is impossible, pharmacotherapy should be initi-
`ated. The lnter_nat_iona1_Rhinitis Management Group
`recommends a symptom-guided approach to the phar-
`macotllerapy of allergic rhinitis.’ Topical intranasal
`steroids provide rapid relief of symptoms of seasonal
`allergic rhinitis with minimal side effects. Therefore,
`they are considered fir_st—_line treatment for this dis-
`ease.
`immunotherapy is only recommended when
`pharmacotherapy does not lead to satisfactory relief of
`symptoms.”
`
`
`
`aterizal ma The rotected b co ri'hl law TltIe17,U.S_.Code
`
`MED_DYM_00000726
`
`

`
`Case 1:14-cv-01453-LPS Document 43-13 Filed 10/22/15 Page 3 of 69 PageID #: 917
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`°
`
`"
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`'DOCUFlT€TTl'
`
`NEW TOPICAL STEROID GICLESONIDE
`
`
`
`'
`
`Figure 1. Structuralformula ofciclesonlobl ‘
`
`'
`
`.
`
`From the safety and efficacy evaluations of ‘reel
`cal tests, it was concluded that 200 mg cicl ‘
`'
`nostril would be a reasonable dosage for .
`administration in subjects with allergic _rhi_:n
`
`METHODS
`
`Overall Study Design
`
`The study was conducted as a randomieetl;-4'j)lac:§éliO:?
`controlled, double-blind, two-period crcss_o'y'er‘t
`at-'
`Ciclesonide and placebo were given‘ fort§_7_c.’tlii. '_s'oat§l1_;
`Both tr_e'a_trnjent periods were separated hyyaf fiiasl1o:'
`period of at least 14 days. Controlled intranasaI=a1
`gen" p1"o'vocation with c'omm'ercia1ly arr ' abl '
`-extracts was performed on the 2 days;be'l'ore tl;
`the respective treatment periods [study.'tlays' 4
`
`
`
`'
`
`
`
`
`
`--
`
`itching, anderhiriorrliea were assessed."bjy"tr1e,
`standardized visual analog scale as descr ilIed'._b.E.
`
`The-two different assessment time points "were -
`oil,"
`be'.Cause of the known variability in the time courses of .
`the patients’ response to the allergen challenge,"
`" '
`
`:1.-
`:.5
`
`Subjects
`
`Twenty-four subjects (13 males, 11 females] ‘with. a
`history of allergic pollen rhinitis-but free of symptoms
`at screening entered the study and were randomly
`
`1 053
`
`ateriai ma be roteoted b co ri'ht law Title 17, U,S..Code
`
`MED_DYM_00000727
`
`‘Ciclesonide is a new steroid under clinical develop
`The ciclesonide molecule has a chiral center in
`
`etal side chain. The two epimers of the ‘com-
`are clearly different in their receptor affinities
`metabolization rates. The-R-epimer of ciclesonlde
`_gore 1) has a considerably higher binding affinity to
`érglucocorticold receptor as compared to the-
`plrner. and -therefore only R—cielesonide is dev'_el—
`_i=_.'.d for "clinical use. This separation of epimers can be
`garrled as an essential progress in the development
`pical steroids, In vivo, ciclesonide represents a
`prodrug that is cleaved locally to achieve topical
`isffects..
`
`The safety and toierahility of ciclesonide have been
`amlned in a variety of preclinical tests investigating
`acute and chronic toxicity in different species. The
`.
`"anti-inflammatory potency of ciclesonide has been
`own in various functional in vltro studies {s.g., inhi-
`bltion of concanavalin A~ind'uced proliferation of rat
`teen‘ cells] and irrvaricus preclinical in viva inflam-
`.
`_
`n_1_at_1on_ models such as the rat cotton pellet test.
`Ciclesonide was very well tolerated when .a‘cl_'r'ninis~
`feted to healthy subjects in clinical phase I_ studies,
`fiend suppression of the endogenous cortisol release
`. wa.s'mim'1naI.
`From the preclinical findings. it was presumedthat
`1
`' administration of ciclesonide shows high local ceffi~
`V. cacy in patients with allergic rhinitis while systemic
`-3 side effects are minimized. Therefore, the present
`a study investigated whether intranasel adniiriistratlon
`of ciclesonide attenuates the symptoms of allergic
`rhinitis as compared to placebo. Secondary objectives
`were safety and local tolerability.
`
`CLINICAL TRIALS
`
`d '
`t
`‘
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`
`
`
`

`
`Case 1:14-cv-01453-LPS Document 43-13 Filed 10/22/15 Page 4 of 69 PageID #: 918
`-e-145s-L-Ps-- no-cu-me-ms--4-e-=1-e--------Filed -10/22/15 Page 4- 0f'69'Page|D #.
`
`SCHMIDT ETAL
`
`allocated to the two treatment sequences [ciclesonidel
`placebo. placebo/ciclesonide), which comprised 12
`subjects each. The median age of the study partici-
`pants was 28 years. and their median body weight was
`76 kg.
`Inclusion criteria were the following: history of sea-
`sonal allergic rhinitis, positive skin -prick test, reduc-
`tion of mean rhinai airflow after allergen provocation
`by at least 25% measured by rhinomanometry, andage
`between 18 and 45 years. Exclusion criteria were the
`following: any active disease or relevant abnorrnalities
`as ascertained in a prestudy examination, abnormal
`ENT (ear, nose, and throat] status (e.g., relevant sep-
`tum deviation), symptoms of allergic rhinitis at screen-
`ing. history of asthma attacks or severe anaphylactic
`reactions, any history‘ of drug allergy, any-medication.
`no more than 2 weeks before the start of-the study, and
`topical or systemic antialiergic medication, including
`steroids or decongestive nose drops no more than 4
`weeks before the study. Subjects were not allowed to
`smoke more than _10 "cigarettes per day or to drink alco-
`hol or coffee excessively. In -addition, the following
`exclusion’ criteria were taken into account for women:
`no reliable contraception in the oyclelbefore the study.
`during the study period, and the cycle after the study
`[only IUD or registered hormonal contraceptives were
`allowed}; pregnancy; or lactation period.
`
`Screening Procedure and Allergen Provocalion
`
`All subjects underwent a comprehensive medical
`examination no more than 2 weeks prior to inclusion
`into the study, This screening examination comprised
`medical history -and physical examination. including
`nose and throat, 12-lead ECG, body temp erature, clini«
`callaboratory parameters, and asldn prick test using a
`standard battery of 20 common aeroallergens-. Only in
`case of positive skin prick test was a rhinomanornetry
`carried out to obtain a baseline rhinal flow value, and
`immediately afterward controlled antigen delivery
`with commercially available poilen extracts {Aller-
`gopharrna Ioachim Ganzer KG, Reinbek, (3e'1_-many] was
`performed by spraying two puffs of the pollen suspen-
`sion in each nostril. The pollen extracts werefprepared
`individually for each subject by choosing the one or
`two allergens that had evoked" a" major. reaction in the
`skin prick test during the screening en-‘zamination. For a
`particular subject, the same kind of allergen was us_ed
`during the whole study. Nasal congestion was objec-
`tively assessed by standardized rhinornanometry
`using commercially available equipment (‘manufac-
`turer: Allergopharma Joachim Ganzer KG, Reinbek,
`Germany). The right nostril was generally tested before
`
`1064 0 }Clin Pharmncol 1999;39:10B2-1069
`
`the left one. Rhinal airflow was determined as the sum
`of both values obtained at a pressure difference of :15:
`Pa. The rhinal flow values at 5 and 30 minutes aftert ’
`allergen provocation were averaged prior to furtlie
`analysis. The percen_tags_ fall between the precise’
`value (i.e., the resulting value for both nostrils} and ti;
`averaged value after allergen provocation served as
`inclusiozl criterion. A sub}‘_ec_t was only included int
`the study if the rhinalflow decreased by at least 25*?‘
`after allergen provocation at screening. In case a pai-
`ticular allergen that had produced a major reaction 1‘
`the prick test failed to cause a nasal reaction, and if iii
`result of the skin prick testhad shown multiple sensi
`tivity, the nasal provocation test could have bee
`repeatedwithanother-allergen that had caused a ma
`skin reaction in the prick test.
`
`'
`
`Study Medication
`
`Ciclesonide was administered using pressurize
`metered dose inhalers [MDI} with an attached nssa
`adapter. Eacl1,puf_f of released aerosol contained 200 it
`cicle$_0ni.de. Placebo was administered using a devic
`‘Pcr‘I--H
`of identical appearance to facilitate the -doubl
`'
`_-
`conduct of the study.
`No concomitant medication was allowed during th
`study, except for the treatment of severe headache fo
`which a 1im_ite'd amount of paracetamol [up to 1 g pe
`day) might be taken.
`
`Course of the Study
`
`In each treatment period, the study medication we
`a_d_m_iniste_red for ‘.7 consecutive days [study days 1 to;
`7} at about 8:00 am. in the presence-of the investiga.-‘
`tor. One ‘puff of aerosol containing 200 fig ciclesonide_'
`or placebo was given into each nostril. The subjects
`had to ‘breathe in continuously while the puff was
`reieased. Controlled "antigen delivery was performed?
`at 10:00 a.m. for 9' consecutive days [study days —-2 to‘
`7} in each study periodby spraying two puffs of the‘
`pollen suspension into each nostril. At 5 and 30 min:
`utes after each ailergen provocation, subjective nasal
`symptoms {obstru'ct'1on, ‘itching-, rhinorrhea) were
`evaluated, and rhinomanomet-ric measurements were
`performed.
`The three subjective symptoms were assessed by
`means of a standardized visual analog scale. An ade-
`quate position had to be marked by the subjects on a
`line between the two limits‘ "not in existence" and
`"very strong." The lengthof-the line was 10 cm, and a
`score number [value between D and 10] was ascertained
`by measuring the distance in cm from the beginning of
`
`
`
`. ateria! ma be rotected_b co rihtlaw Tit|e‘l7.U-.S.CocEe-j
`
`MED_DYM_00000728
`
`

`
`Case 1:14-cv-01453-LPS Document 43-13 Filed 10/22/15 Page 5 of 69 PageID #: 919
`3-—-I;-PS’ ‘Document 43-13 F'i'|'ed'10/22/1"5“‘"“'age"“5*of"69"Pag'e|'D #:"i919“'*‘““"'""“’
`
`NEW TOPICAL STEROID CICLESONIDE
`
`the "time points 5 minutes and 30 minutes after aller-
`gen provocation since the itching and rhinorrhea
`scores were generally lower at 313 minutes as compared
`to 5 minutes {in contrast to rhinal airflow and the
`obstruction score for which similar values were
`obtained). No adjustment of the oz-level was made for
`the testing" ofthese multiple secondary variables due to
`their exploratory nature.
`Results of safety measurements at pre— and final
`cl_1'ecl_< were analyzed in a merely descriptive manner.
`Clinical labioratory data were presented on an individ-
`ual basis and were marked according to the normal
`ranges. Nature, incidence,
`intensity," and causality
`assessment were reported for each adverse event.
`lnthis crossover study, the iriirasubiect coefficient
`of variation for the primary variable rhinal flow was.
`approximately 35%. The chosensarnple sizeofN = 24
`subjects was sufficient-to ensure apower of 80% in car-
`rectly declaring a change of 20% versus placebo as
`being significant at the 5% level, two—sided.
`
`0rga.niz,a.ti.'on of the Study
`
`The "study was conducted according to the revised
`Declaration of Helsinki, in compliance with the Ger-
`man. Medicines Act and the requirements of good
`clinical practice [GCP}'." The subjects were given com-
`prehensive verhal and written information about
`objectivesand possible risks of thestudy. They gave a
`written informed consent before the start and" had the
`right to withdraw from the study at any time, even
`without’ giving the reasons. The study protocol. was
`approved by-the independent Ethics Committee-ofthe
`Faculty of.Clinic.a1 Medicine Mannheim of the.-Univer-
`sity of Heidelberg. The clinical part of the study was
`conducted at the Mannheim University Hospital, Ger-
`many. The [study was sponsored by Bylc Gulden Phar-
`maceuticals, Konstanz, Germany.
`
`RESULTS
`
`All subjects completed the study according to proto-
`col, and no subjects were replaced. The median per-
`centage decrease in rhinal airflow after allergen
`provocation at screening was 40% (range: 26%-34%].
`
`Eiftc_a'cy-Analysis
`
`The time courses of geometric mean rhinal flow values
`[averages of 5 and 30 minutes] and SEM are plotted in
`Figure 2. On study days -2 and «-1 [run-in phase with
`allergen challenge]. the rhinal airflow was equivalent
`between ciclesonide (geometric mean: 508 and 520
`
`1055
`
`econdary variables were the subjective nasal find-
`nge of obstruction, itching, and rhinorrhea. Obstruc-
`on was analyzed in analogy -to the rhinal flow as both
`at-ameters provide information about the: symptom.
`
`nd the obstruction score as a subjective parameter.
`or the -itchingand rhinorrhea scores ascertained on
`tudy day 1?, 95% confidence limits were calculated for
`Qthe difference ciclesonide-placebo using an additive
`‘model. This evaluation was performed separately for
`
`CLINICAL TRIALS
`
`-
`
`alt--‘tlal ma be r0teG,ted._b co rihilaw Title 17-, U.S.Code
`
`MED_DYM_00000729
`
`"(position “not in existence”) to the position
`"At each measuring time point, the assess-
`f.. the subjective findings, which comprised
`"strils, was implemented prior to the rhinorna-
`in "measurements because the local. manipula-
`W
`4 t have ternporarily influenced the outcome
`ymptoms.
`and local tolerability of ciclesonide were
`33 by continuous recording of adverse events
`afety measurements at final check. The
`py examination, including an ENT check, was
`" d..:_r'io more than 2 weeks after the end of the
`at art [of the study.
`olunteers visited the study site at about 9:45
`udy days -2 and 4 and at about_ 7:45 am. on
`s
`to ? inboth treatment periods-. The-study
`on ucted under controlled conditions. A physi-
`s on duty during the entire study course. Before
`aubj'ects left the ward at about 11:60 a.m., the state
`”
`health was confirmed by the responsible
`tlgatcr.
`
`atistical Methods
`
`"ircary ‘variable for confirrnative biostatistical
`3- was the rhinal airflow determined by rhino-
`'"‘ornetry._ Toestablish comparability of the pretreat-
`values, 96% confidence limits for the ciclesonitiel
`be ratios of population medians were compared
`' "conventional equivalence acceptance limits of
`.. o 1.2593" on days -2 and -1. On treatment days 1
`' he comparison of the rhinal airfiow was doneby
`are of the analysis of variance. (ANDVA) for the
`étreatment, two-periofl crossover design after loga-
`‘rnic transformation. Geometric means and two-
`" 9.5% confidence intervalswere presented for the
`ctive ciclesonicie/placebo ratios in ‘addition to -
`ypothesis testing; Treatment differences on the 7
`ays were tested by means of a closed testing proce-
`'
`as without need to adjust the ot—1evel:“ first day 7
`d, if there was a significant difference between
`
`
`
`

`
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`SCHMIDT ET AL
`
`
`Ea c
`
`E E
`
`.
`.5
`
`m’ 5*‘ on days -2 and «-1, respectively] and placebo
`(501 and 490 cm‘ s“)- as the respective 90% confidence
`intervals of 0.86-1.19 and 0.92-1.23 were entirely
`within the equivalence acceptance limits of 0.80 and
`1.25. The respective geometric means for the
`cictesonictelplacebo ratio were 1.01 on day -2 and 1.06
`on day -1.
`On study days 5. 6. and ?, the geometric mean rhinal
`airflow was at least 30% higher under treatment with
`ciclesonide nasai spray as compared to placebo [Fig-
`ure 2, Table I), andthis effect was statistically signifi-
`cant. For the rhinal airflow values ascertained‘ on study
`days 1 to ‘:7, geometric-means and 95% confidence lim-
`its for the ratios ciclesonitie/placebo are summarized
`in Table I. Significant increases in rhinal flow [33 <
`0.05, two-sided] are-reflected by 95% confidence inter-
`vals that are entirelyabove 1.-
`The time courses" of -geometric mean scores and
`SEM.for the subjective symptom obstruction {-averages
`of 5 and 30 minutes} are plotted in Figure 3. The
`obstruction score was equivalent on study day -1 as
`the 90% -confidence interval for the ratios ciclesonidel
`placebo of 0.82-1.12- was entirely within the equivaa
`lance acceptance limits of 0.80 and 1.25. On day -2,
`the 93% confidence interval of 0.86-1.28 marginally
`exceeded the -upper equivalence -acceptance limit of
`1.25. However, in view of the higher variability of sub-
`jective assessments of nasal potency, a wider equiva-
`lence range than the conventional one of 0.80-L25
`may be appropriatefor the assessment of comparable
`pretreatment scores. Therespective geometric means
`for the ciclesonjde/placebo ratio were 3.05 on day —-2'
`and 0.96 on day -1.
`
`1066 I I Clin Phermacol 1999;3_9:1Dti2—1(369
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`-' ater_i_at me be rotected b co r'i' htlaw Title 17. U.S_..Gode
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`MED_DYM_00000730
`
`‘time course of*rh1'nalflow (geom
`Figure 2.
`tic mean and SEM. N = 24} after controlled
`Iergon challenge (5 and-30 minutes.a1;rer'
`'
`before treatment (days -2 and -1} and d
`tr_eatment.(duys 1 to 2} with 4OU‘;:,g aides‘
`[solid _d;'_arno1_1ds} and -place_bo_ (open d
`1’1fl_DI_l_d5}. Theprestu dyvalues before (P) and
`—i'er {<1} allergen challenge are inserted on the
`left.
`
`Table I Geometric Mean [N = 24} of Rhinal
`Airflow {cm3 3“) {5 and 30 minutes averaged)
`for Ciclesonide and Placebo and Geometric
`Mean and 95% "Confidence Limits for the
`Ratio‘ Ciclesonide,/Placebo
`
`Rhino! Airflow tcm‘ s")
`Ciclesanide/Placebo
`Geometric:Mesn
`Ti-esuuent ——-————-——.—-—:
`Geometric Mean
`
`Day
`Ciclesonide
`Placebo
`(95% confidence limits} :
`
`1
`2
`3
`4
`5'
`6
`7
`
`537
`540
`497
`561
`583
`615
`589
`
`510
`468
`480
`520
`447
`452
`45.4
`
`1.05 (0.37-1.27")
`1.15 (0.98.-1.36]
`1.04 (0.85-1.26}
`1.03 {o.ao—1.3.o}
`1.30 (1.02-1.67}
`1.36 (1124.64)
`1.30 (1.07-1.57}
`
`Ciclesonide significantly (‘p < 0.05,’ two-sided) _
`reduced the obstruction score from study day 2 to I
`study day 7."I"his-isreflecteid in 95% confidence inter
`vals for the. ratios ciclesonide/placebo, which are .
`entirely less. than I (Tobie II].
`_
`On all study days from day 2, the median itching -4
`and -rhinorrhea scores during ciclesonide treatment -
`were below those obtained during placebo treatment
`at either measuring-time point. With increasing dura-
`tion 0'1‘-treatment, the. medianitching and rhinorrhsa
`scores further declined under treatment with
`ciclesonide. On all study days. higher median itching
`scores were ascertained at 5 minutes rather than at 30
`
`
`
`

`
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`-A - --1453-LPS ’ Document 43-1'3 ""‘F'i|ed 10/22/15”“ Pagec7c'*er6e'''P'e:j'e’r'D #: *9'2":L"—““l '-
`
`NEW TOPICAL SWROID CICLESONIDE
`
`_ Geometric Mean (N = 24} of the Subjective
`ptom Obstruction [5 and 30 minutes averaged]
`-liclesonide and Placebo and Geometric Mean
`95% Confidence Limits for the Ratio
`_Cicl_esonide[Placebo
`
`9331
`"
`
`Obsh-uction
`{symptom score;
`Geometric Mean
`
`
`r pielesonide
`3.6»
`3.2
`3.0-
`2.9
`2.2.
`2.1
`1.9
`
`Placebo
`3.6
`4.1
`4.2
`4.1"
`4.0
`3.7
`4.‘!
`
`'23.
`
`_
`Ciclesonidell-"fanatic
`Geometric Mean
`(95% sonfidencelimits)
`1.00 (0.76-1.32)
`(2.75 (0.64-o.e1_)
`0.73 {o..s9~.o.'a.s)
`0.71 (0.56-0.91}
`0.56 (0.41-6.75}
`0.53 {U'.42-8.76}
`0.48 (0.33-GL70]
`
`35313;
`5'
`rcgg»
`"flung
`j°f;}‘:f
`mg
`‘
`an cm‘
`
`values of hematological and clinical chemistry
`parameters remained "essentially constant during the
`study. Some minor deviations from the reference range
`were without clinical relevance and remained within
`the range" commonly observed in clinical trials. The
`following adverse-events-arose during the study in 1
`subject eac'h:. lumbalgia, infectious rhinitis, biliary
`pain, tonsillitis, and_dia1_'rhea. All adverse eveniswere
`considered to be not reletedio the study medication.
`No signs of local mucosal irritation occurred.
`
`Discussion
`
`Standardized measurement ofrhinal airflow by rhino-
`r'r_'1__anometiy.is a c'ommon'_die'g:o'ostic method for the
`quantitative-assessment of i_r.I.1p.aired nasal -ventilation.
`and it-is being increasingly used as a__pha'nna_cody-
`-namic model to evaluate the efficacy of newly devel-
`oped antiaiiergic drugs. During this_s_tudy,_the rhin'oma-
`nornetric measurements wereperforrned according to
`the recommendations given by the “Committee Report
`on—Standerdizaiion of Rhinornanometiy.”‘3 lthas been
`shown "that -the ciinical efificacy of topical‘ steroids
`administered as. nasal spray can be quantitatively
`assessed by rhinomanometryf‘ the use of -symptom
`scores "is aiso an accepted and common method.” A
`significant correlation between the resnits of the-sub—
`ieictive and objective assessment ofnasal obstruction
`has been shown,“ hut there have also been reports that
`the rhinomanometric -measurements of nasal airflow
`do not always reflect the patient’s sensation of nasal
`obstruction." Therefore, in the present study, the inten— ’
`sity of suhjective nasal symptoms was determined in
`
`‘lime course of omtmction score
`Figure 3.
`{geometric mean and SEM, bl *-= 24) after con-
`trolled allergen "challenge (5 and 30 rninutes
`averaged} before treatment (days -2 and -31}
`and during treatment (days 1 to 7) with 4:90 pg
`ciclesonide (solid circles) and placebo (open
`circles].
`
`‘£067
`
`after theallergen challenge, independent of
`th r‘t_he subjects received placebo or- the active
`on :d. On day 7, treatment with ciclesonide led
`gnificaiit improvement of itching and rhinorrhea
`5 minutes and 30 niinutes after the allergen
`"e" ('Ihb1e=Ili).
`'
`
`r'1d_I.o_cal Tolerebility
`measurements at final check revealed no clini-
`\
`ll significant findings. Individual and median
`
`-2
`
`-1
`
`1
`
`2
`
`3
`Day
`
`4
`
`CUN iCAL TRIALS
`
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`
`MED_DYM_00000731
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`l .
`
`1
`
`b0
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`nits}
`,)
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`I}
`
`:}
`'}
`
`ded)
`2 to
`
`star-
`are
`
`hing
`neat
`rient
`ma-
`
`rhea
`vith
`hing
`1t3U
`
`
`
`

`
`Case 1:14-cv-01453-LPS Document 43-13 Filed 10/22/15 Page 8 of 69 PageID #: 922
`'”Case'1':1'4'—'c'v-01453-LS ‘Document 43-13 --Fi-|ed“1~O/*2-2/1-5 Page 8 of 69Page|D-:
`
`"
`
`SCHMIDT ETAL
`
`
`
`Table III Mean {N = 24] Symptom Score for Itching and Rhinorrhea on Day 7 at 5 and 30 Minutes
`and Mean and 95% Confidence Limits for the Difference Ciclesonide-Placebo
`
`Symptom Score Mean
`
`Symptom
`
`Itching
`
`Rhinorrhea
`
`Time
`
`Cislesonide
`
`Piaeebo
`
`Ciclesonide-Placebo Mean (95% confidence limits]
`
`5 minutes
`36 minutes
`5 minutes
`30 minutes
`
`2.7
`0.7
`2.6
`0.3
`
`5.0
`2.1"
`4.1
`2.4
`
`-2.3 (-3.1 to —1.5)
`-1.4 («-2.4 to —o.5)
`-1.5 {-2.7 to -no.4)
`-1.6 (-2.6. to -9.7)
`
`
`
`itching-and rhinorrheakat an early time point seems"
`he p_articu_larly useful during as study testing drug’ of
`easy. It shouid be noted, "however, that a signiizlcg
`treatmeiit effect of ciclesonide on itching and rhino
`rhea could also be stated for the later assessment tim
`point of 30 minutes, even though the ‘symptoms we"
`only mildly pronounced. These findings confirm hi '
`drug" efficacy and "good reliability of data.
`'
`Topical treatrnent of allergic rhinitis with cortico
`teroids tinhibits-allergen-induced early and late nas
`resp_onses';‘° it is thought that the early phase of allerg
`reaction is usually suppressed only after long-tor‘
`treatment, whereas the i.mp'rove,men_t_of the late pha
`is seen earlier. The surrogate parameter used in th
`study. -nasal obstruction, is a. symptom of the e
`phase; in contrast to former experiences, however,
`already improved on the second day of treatment. Th
`may underline the potent local efficacy of intranas
`ciclesonide in allergic rhinitis.
`A direct comparison of the results of this study to lit-5‘
`erat-ure data obtained with other steroids is difficult
`
`becauseof substantial differences in the study designs;
`Several points have tube "taken into consideration——fo1‘-
`example, primary variables {objective/subjective assess-:
`ment of symptoms), sample size, allergen exposure.
`(natural/controlled], and overall statistical plan
`{parallel-group design/crossover design). In the pres-
`ent pilot study, the sample size was limited to 24.
`patients because of the highly standardized study con—
`ditions, the method of controlled antigen delivery dur-
`ing tha allergen-free season,.and the crossover desigi,
`which allows intrainclividual comparison of the active
`compound and placebo.
`A recently published comparative study on the
`influence of lon_g»te1'-m treatment with 200 pg flutica-
`sone propionate once daily on nasal inflammation
`parameters during the pollen season” also used symp-
`tom scores for obstruction, itching, and rhinorrhea. The _
`evaluation of the subjective symptom scores confinned
`
`parallel to the rhinoinanometric airflow measure-
`ments“ because this complementary information may
`provide ainore reiiable assessment of nasal symptoms
`than the objective measurements alone.
`Pharinacoclynainio studies evaluating the efficacy
`of newly developed antiallergic drugs in patients with
`allergic rhinitismay he performed during the pollen
`season, making use of theinatural allergen exposure.“
`Although thisrnethod has the advantage ofova1uat-
`ing nasal symptoms under the petient’s usual living
`conditions, it may result in systematic errors because
`the concentration of airborne ‘pollen grains may fluc-
`tuate considerably during the trial period. A better
`standardization of the study conditions can be
`achieved by controlled antigen delivery during the
`trial, which should be perforrned during the
`allergen—free season to avoid additional exposure to
`airborne allergens.” This study design is particularly
`useful for a first efficacy study witha new antialiergic
`compound and was therefore chosen for the present.
`trial with ciclesonide.
`
`The results of this double-blind, placebwcontrolled
`clinical trial arethe first to indicate that the new topi-
`cal steroid ciclesonide is effective in the treatment of
`
`allergic rhinitis. A statistically significant increase of
`the rhinomanometric-measured airflow was found
`
`from the fifth day of treatment, while the subjective
`impression of the alleviation of obstruction was
`already significant from the second treatmentday. Fur-
`thermore, a statistically significant relief of the allergic
`symptoms of itching and rhinorrhea was demon-
`strated. The intensity of the early allergic symptoms
`[itching and rhinorrhee) was generally more pro-
`nounced at 5 rninutes after allergen provocation than
`30 minutes afterwards-,, independent of whether the
`subjects received ciclesonide, placebo, or no treatrnent.
`Obviously, the allergic symptoms of itching and rhi-
`norrhea improve more quickly after. allergen challenge
`than nasal obstruction. Therefore. the quantification of
`
`1063 e I Clin Pharmacol 1999:39:108-2-1039
`
`aierial ma be rotected b on ri ht law Title 17-, U.S. Code
`
`MED_DYM_00000732
`
`

`
`Case 1:14-cv-01453-LPS Document 43-13 Filed 10/22/15 Page 9 of 69 PageID #: 923
`- --
`:
`'--4—Cv-0-1453‘-'|;P'S' ----Docu-m-em“-21:3-=-rel----t-t-efie r"~; _
`
`i
`
`NEW TOPICAL STEROID CICLESONIDE
`
`
`
`efficacy of fluticasone propionate in the treatment
`easonal allergic rhinitis. The study also demon-
`ted that circulating eosinophils and nasal eosino-
`ia were significantly reduced. Comparable labora-
`parameters were not investigated in the present
`““;:}o't's'tudy, but due consideration was given to the
`
`ctive measurement of rhinal airflow and to" the
`emjiination of the onset of the treatment effect-of
`esonide. The onset of symptom relief during treat-
`nt -with triamcinolone acetonide was investigated
`5 patients with ragweed-induced allergic rhinitis.‘
`iitically apparent onset of action was defined as a
`T ‘decrease in obstruction symptom scores from
`eline. which could already be stated after 1 day of
`tnient. This early onset of action corresponds to‘
`" results ofthe present study with ciclesonide.
`cicleson'ide'is highly effective in the treatment of
`lergici rhinitis and leads to a rapid alleviation of
`ptoms withoutproducing systemic side effects, it
`‘ght he an alternative to oral antihistamines in the
`
`tr'ne.nt.of aIle'r'gic.rhinitis.
`
`Garfield: IM, De" Craafoiifl Veltl '1‘, Nahori MA, Vergaftig EB; van
`V3ij_lc'RG, Zijlsare F}: Interleukin-5 and eoslnophil cationic protein in
`sat lavage-s ofrh_inill.s_ patients. Eu1‘]Pbar'macoI 1'995:275.:2_9s-3 co.
`Pipltprn U, lcallsson G. Enerback-L: The cellular resp_onse.to.i_1_u-
`an "allergic mucosa -to natural allergen exposure. 1Allergy Clin Im-
`ttnol l9Bfl:32:1_O4fi-103,4.
`van Wiik KG. Ziijlstra F}, van Toorcnenbergen AW, Vcnneulen A.
`Dieges Pl-I: An "isolated early response after nasal allergen challenge
`stillicieiit to induce nasal hyperreactivityfinnfilfergy 1992;69:4'3.
`‘Day tn, Buckeridge 131;. Clark RH, Briscoe MP.'PhilJ_ips .12: A ran-
`flomized, double-blind,plecelao-controlled. controlled antigen de-
`livery _s'_ti_idy of the onset of action of acrosoliaed triarnoinolcnc
`'
`'aton'1'tlc nasal spray in subjects wilhjagweed-induced allergic
`r_hinitis.IAHe1gy' Clin Immumbt 19Q6;97:105l]-1057.
`5.-Kozrna GM. Sadik MK, Watraus ML: Economic outcomes for the
`treatment of allergic rhinitis. Pftormocofioonomics 1996;1B:4-13.
`
`6. Sibbalcl E. Rink E: Epidemiology of seasonal and perennial rhinitis:
`clinical presentation andrnerlical history. Tlhomx 1991;46:895-901.
`7. International Rhinitis Management Group