(3 R I G {IV A.L
`
`I E S E A.Fl(3 H
`
`A
`
`
`
`A Comparison of the Efficacy of Fluticasone
`Propionate Aqueous Nasal Spray and Loratadine,
`Alone and in Combination, for the Treatment of
`Seasonal Allergic Rhinitis
`Paul H. Rainer, MD; Julius H. van Baxvel, MD; Bruce 0. Martin, DO; F’i‘(Z«?2i'€ C’. Hampel, Jr, MD;
`William C. Howlrmci, H1’, ME‘; Paula R. Regimes, PhD; Ronald E’. lVesi:l2md; Brittrxri iii Bowers, Ph,a:rmD,-
`and Cindy K. 0001::
`San Antonio, Austin, and New Bzrozzmfeifs, Texas; and Research Triangle Park, North. Ccuvolrlmz.
`
`BACKGROUND.
`
`lntranasal corticosteroids and oral antihistamines are both effective in the treatment of season-
`
`al allergic rhinitis, although the therapeutic value of administering the two types of agents concurrently has rarely
`been evaluated. This study was designed to compare the efficacy, safety, and impact on quality of life of fluticas-
`one propionate aqueous nasal spray (FP ANS), loratadine, FP ANS plus loratadine, and placebo (an aqueous
`nasal spray plus tablet) in the treatment of seasonal allergic rhinitis during the mountain cedar allergy season in
`south central Texas.
`
`METHODS. Six hundred patients with seasonal allergic rhinitis were treated for :2 weeks with either FP ANS
`200 ug once daily, loratadine 10 mg once daily, the FF’ ANS and loratadlne regimens combined, or placebo in a
`multicenter, randomized, double—blind, double-dummy, parallel—group study.
`
`RESULTS. Clinician- and patient—rated total and individual nasal symptom scores after 7 and 14 days of therapy
`and overall evaluations were significantly lower (P < .001) in the FP ANS and FF’ ANS plus loratadine groups
`compared with the loratadine only and placebo groups. Loratadine was not statistically different from placebo in
`clinician and patient symptom score ratings nor in overall clinician and patient evaluations. FP ANS plus lorata-
`dine and FP ANS rnonotherapy were comparable in efficacy in almost all evaluations; for some patient—rated
`symptoms the combination was found superior. Mean score changes in the Rhinoconjunctivitis Quality of Life
`Questionnaire from baseline to day 14 showed significantly greater improvement (P < .001 ) in quality of life in the
`FP ANS group than in the group of patients receiving loratadine only or placebo, and no significant benefit was
`demonstrated in the FP ANS plus ioratadine group over the FP ANS monotherapy group. No serious or unusual
`drug-related adverse events were reported. Combining loratadine with FP ANS did not alter the adverse events
`profile or frequency.
`
`In the treatment of seasonal allergic rhinitis, FP ANS is superior to loratadine and placebo, and
`CONCLUSIONS.
`adding loratadine to FP ANS does not confer meaningful additional benefit.
`
`KEY WORDS. Rhinitis, allergic, seasonal; loratadine; antihistamine; fluticasone propionate aqueous nasal spray
`[non-MeSH]. (J Fam Pract 1998; 42118-125)
`
`ntranasaily administered corticosteroids and
`nonsedating, second—generatlon oral antihista-
`mines currently form the core of pharma-
`cotherapy for seasonal allergic rhinitis.” Both
`treatments have been shown to alleviate or sig-
`nificantly reduce the rhinorrhea, sneezing, and nasal
`itching characteristics of allergic rhinitis? While
`intranasal corticosteroids reduce nasal blockage
`more effectively than oral antihistarninesfi antihista-
`
`Suhnmtted, rrzeisea‘, Mag: 7’, 1998. From Syloam Research, San
`Animate, Taxes (RH.R.); Aiéerggg Associates oj’Aust2‘n
`Diagiwsiiic
`{J.I:l'.i’.') and i’1‘eoizieQaesiResea'reh, (W CH),
`Austin, Terms; Southwest Alierggg and Asemna. Research.
`Center, San Antonio, Texas (B.G.M.}; and Central Texas
`Health 1i’esearr'ch, New Braunfels (EC.H.); Gibxo Wellcome Inc,
`Research Triaizgle Park, North Carolina (RE. lrif, .8. W8,
`I’.R.R., GK. 0.). Requests for reprints should be addressed :0
`Paul H. Rome); MD, Sylvrma. Research, 7711 Louis Pasteur
`Brice, Suite 406, San Antonio, D’ 78229.
`
`mines tend to have a more pronounced effect on eye
`symptoms.” The choice of one mode of pharma-
`cotherapy over the other is generally based on patient
`preference, with the goal of achieving the most effec-
`tive control of rhinitis symptoms with the fewest side
`effects.
`
`One currently available intranasal corticosteroid
`preparation, fluticasone propionate aqueous nasal
`spray (FP ANS) (Flonase Nasal Spray, 0.05% wfw,
`Glaxo Wellcome Inc, NC), was developed to provide a
`high ratio of local anti-inflammatory to systemic activ-
`ity.“ In clinical trials of 2 to 4 weeks’ duration com-
`paring FF ANS with oral antihistamines, FP ANS
`demonstrated significantly greater effectiveness than
`loratadinefl‘ terfenadine,‘3‘“ astemizoleflt and ceil-
`rizinel“ in relieving nasal symptogs of rhinitis.
`Drouin and colleagues” have suggested that the
`concomitant administration of an intranasal cortices‘
`
`teroid regimen with an oral antihistamine regimen
`
`theoretica
`nasal and
`with eithe:
`ale ha“?
`beclometl
`oral antih
`an F1” AN
`no studies
`and lorat:
`to compa
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`loratadini
`treatment
`tis due to
`
`PATIEN
`Male am
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`years or
`moderate
`accordin
`scored 0
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`reaction
`within if
`consiste:
`1:13; (3) a
`toms f0]
`seasons;
`rhinitis l
`a run-in
`had rec
`with 10]
`weeks,
`counter
`rhinitis
`within ‘E
`ticoster
`either 2
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`polyp 1;]
`Spray. I
`of nasz
`Patient
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`cant pl
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`STUD
`The pr
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`1 1 8 The Journal of Family Practice, Vol. 47, N0. 2 (Aug), 1998
`
`© 1998 Appleton & Lange/ISSN 00943509
`
`
`
`Exhibit 1034
`IPR2017-00807
`ARGENTUM
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`000001
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`K medication received both a placebo nasal spray and
`active oral medication, and patients randomized to
`active nasal spray received both the active nasal spray
`and placebo oral medication. At the screening visit,
`clinicians evaluated potential study candidates by rat-
`ing their nasal symptoms (sneezing, nasal blockage,
`rhinorrhea, and nasal itching) according to a visual
`analog scale, ranging from 0 (absent) to 100 (severe)?
`and by completing the following: a medical history,
`skin testing for allergy to mountain cedar allergen (if
`not done within previous 12 months), a physical exam-
`ination, clinical laboratory tests, pregnancy test, and
`an examination of the nose and oropharynx for evi-
`dence of Candida. Patients who had symptoms began
`the 7- to 30-day run-in period immediately after screen-
`ing, and patients who were free of symptoms were
`instructed to record their allergy symptoms associated
`with mountain cedar as soon as they began, so that the
`run-in period could be initiated.
`During the run-in period and throughout the study,
`patients used the visual analog scale described above
`to rate their nasal symptoms daily on diary cards.
`Symptoms were rated in the evening to represent
`symptoms for the entire day. To qualify for enrollment,
`the total nasal symptom score (derived by adding indi-
`vidual symptom scores for nasal blockage, rhinorrhea,
`sneezing, and nasal itching for the day) was required to
`be at least 200 of a possible 400 on 4 of the 7 days
`immediately preceding enrollment.
`Patients who met
`this criterion were randomly
`assigned on day 0 (baseline) to receive one of four reg-
`imens for 14 days: FP ANS 200 11g (two 50-iig sprays
`per nostril) plus one placebo capsule (to match the
`loratadine dosing form) once daily at 8 AM; placebo
`nasal spray (two sprays per nostril) plus one encapsu-
`lated loratadine 10-mg tablet once daily at 8 AM; FP
`ANS 200 ug (two 50-pg sprays per nostril) plus one
`encapsulated loratadine 10-mg tablet once daily at 8
`AM,’ placebo spray (two sprays per nostril) plus one
`placebo capsule once daily at 8 AM. The formulation of
`loratadine used for encapsulation was Claritin tablets-
`(Schering Corporation, Kenilwoith, NJ). Dissolution
`testing confirmed that active capsules were compara-
`ble with unencapsulated tablets.
`
`EFFICACY ANALYSIS
`Patients recorded their nasal symptoms and use of
`study medication daily on diary cards throughout the
`treatment phase. Nasal symptoms were assessed by
`the clinician on day 0 (before the first dose of drug was
`administered), day 7, and day 14. During the treatment
`period, patients were not permitted toiuse any other
`medication that might affect rhinitis symptoms. At
`every clinic visit, clinicians recorded the occurrence of
`adverse events (defined as any untoward medical
`occurrence, drug-related or not), recorded concomi-
`tant medications used, checked compliance by diary
`
`The Journal of Family Practice, Vol. 47, No. 2 (Aug), 1998 1 1 9
`
`If
`
`iheoretically should resultcin greater relief of both
`nasal and ocular rhinitis symptoms flianis‘ achievable
`with either regimen alone. Although several clinical tri-
`als have
`evaluated the efficacy of
`intranasal
`beclomethasone dipropionate in combination with an
`oral antihistamine,‘“9 and one study has investigated
`an FP’ANS—cetirizine combination,” there have been
`no studies to date evaluating a combination of FF ANS
`and loratadine. The purpose of the present study was
`to compare the efficacy, safety, and impact on quality
`
`,2
`.
`7
`
`JD‘
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`’ PharmD’
`
`la
`
`t °f SeaS°"-
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`3/ has rarell’
`3 °f flUfiCa3'
`CIUGOUS
`season In
`
`
`l
`
`of life of FP ANS, loratadine, FP ANS combined with
`
`loratadine, and placebo over a 2-week period in the
`treatment of nasal symptoms of seasonal allergic rhini-
`tis due to mountain cedar pollen.
`'
`
`METHODS
`
`P ANS,
`icebo In a
`
`‘ of th
`erapy
`3
`iglcgézio in
`US l0rata_
`Hated
`/ of Life
`of me in the
`Enefit was
`
`’r Unusual
`59 events
`
`acebo and
`’
`
`asa] spray
`
`_
`feet on eye
`3f phar_ma’
`1 on patlent
`most effec-
`fewest side
`
`tlcosteroid
`30“ nasal
`"0570 ‘W/W:
`3 plrovlde 3
`emic activ-
`
`years or older, were eligible for the study if they had
`
`PATIENTS
`I Male and nonpregnant female outpatients, aged 12
`[ moderate to severe seasonal allergic rhinitis diagnosed
`according to four criteria: (1) positive (a 2+ reaction,
`scored on a scale of 0 to 4, defined as a wheal diame-
`ter at least 3 mm greater than diluent control) skin test
`reaction to mountain cedar (Jumlperus ashez) allergen
`within 12 months; (2) appearance of the nasal mucosa
`consistentvvith a diagnosis of seasonal allergic rhini-
`tis; (3) a history of seasonal onset and offset of symp-
`toms for at least two previous mountain cedar pollen
`seasons; and (4) moderate to severe symptoms of
`rhinitis evidenced by patient diary card ratings during
`a run-in. Patients were ineligible for the study if they
`had received, before the screening visit,
`treatment
`with loratadine within 1 week, astemizole within 6
`weeks, cromolyn sodium within 2 weeks, over-the-
`
`’
`
`counter or prescription medications that could affect
`rhinitis symptomatology (eg, nasal decongestants)
`‘ Within 72 hours, or inhaled, intranasal, or systemic cor-
`ticosteroids within 1 month. Patients could not have
`either a septal deviation (>50% blockage) or a nasal
`polyp that could obstruct penetration of an intranasal
`spray. Patients were not included if they had a history
`of nasal septal surgery or nasal septal perforation.
`Patients were excluded if they had clinically signifi-
`cant physical examination findings at screening, had
`evidence of candidal infection, or were pregnant or
`lactating. Patients were also excluded if they had any
`condition or impairment that might affect their ability
`to complete the study or provide informed consent.
`'
`~
`
`’
`
`ation °0m-
`" FP ANS
`eness than
`_and Ceti'
`’t‘s-
`d that the
`_
`Ll c°"t_1C°_$'
`e regimen
`
`STUDY DESIGN
`The protocol for this double-blind, placebo-controlled,
`parallel-group comparative trial was approved by an
`institutional review board for each of the five study
`sites. All patients or their guardians gave written
`informed consent. This study was a double-dummy
`_ design'~in which patients randomized to active oral
`
`_
`
`;
`
`.
`
`000002
`
`

`

`
`
`FP ANS
`+ Loratadine*
`we
`42.2
`15-78
`
`
`
`MeanScore
`
`74 (49)
`75 <51)
`
`120 (80)
`25 (17)
`4(3)
`
`98-0
`982
`5 (3)
`0(0)
`1 (<1)
`2 ( 1)
`2 ( 1)
`
`Placebo Loratadine*
`we
`we
`42.0
`40.1
`16-74
`15.10
`
`61 (47)
`8959)
`
`69 (46)
`81 (54)
`
`115 (77)
`30 (20)
`5(3)
`
`-110 (73)
`28 (19)
`12(8)
`
`97-5
`979
`10 ( 7)
`3(2)
`2(1)
`4 (3)
`1 ( i)
`
`97-O
`968
`8 (5)
`2(1)
`0 ( 0)
`3 ( 2)
`3 (2)
`
`FP ANS*
`we
`40.7
`18-80
`
`58 (45)
`82 (55)
`
`117 (78)
`22 ()5)
`11(7)
`
`978
`979
`8(5)
`3 ( 2)
`0(0)
`4 ( 3)
`1 (<1)
`
`Numeereeawnw
`Mean age, yr
`Range
`
`S9><1fi0-(%)
`Mae
`Fema'e
`Ethnic Origin’ no (%)
`White
`Hispanic
`other
`
`C0mP‘ia“CeT(%)
`With Capswe
`Wm‘ Spray
`Patients withdrawn, no. (%)
`Adverse event
`Famed to return
`Lack of efficacy
`Other
`
`TABLE 1
`
`Demographic Characteristics and Disposition of Patients
`
`FLUTICASONE VS LORATADINE IN RHINITIS
`
`card and capsule counts, and exam-
`ined patients for evidence of nasal
`and oropharyngeal Candida. On day
`14, clinicians and patients indepen—
`demly recorded their Overall eVa1ua_
`€‘J;?.i°§ ¥f§31‘§‘31‘i§‘§’1$‘$‘i;‘§§.§i‘§£‘§i1;‘ETi‘”
`
`QUALITY—0F-LIFE ANALYSIS
`At baseline and on day 14, patients
`completed the Rhinoconjunctivitis
`Quality
`of
`Life Questionnaire
`(RQLQ)? This 28—item, se1f—adminis-
`tered, disease—specific questionnaire
`measures quality Of life globally and
`across
`seven
`different
`domains
`known to be affected by rhinocon-
`junctivitis: nasal
`symptoms;
`eye
`symptoms; activities; practical prob—
`, lems; sleep; emotional
`issues; and
`symptoms other than those involving
`the 11059 01‘ eyei Such 35 fatigue, i1‘H'*
`tability, and tiredness. Patients were
`asked to rate each item on a 7-point
`scale (where 0 = not troubled or none
`of the time and 6 = extremely troubled
`or all of the time), capturing the
`impact of I-hinoconjunctivitis for each
`Item Over the plevlous 7 days. Each
`domain provides a scale score, and
`the mean of all the items provides an
`overall global score. An improvement in rhinoconjunc-
`tivitis quality of life was indicated by a decrease in
`domain and global scores at day 14.
`
`ANS = flutioasone propionate aqueous nasal spray 200 pg daily; loratadine dosage is 10 mg once
`T Pércent of patients who took at least 80% of study medication.
`
`STATISTICAL ANALYSIS
`All patients randomly assigned to treatment received
`at least one dose of the study drug, and reported base-
`line scores were included in the analysis. Patients
`remained in the analysis (daily and weekly timepoints)
`until their efficacy scores were missing because of
`withdrawal or loss to follow-up. All tests performed
`tested two-sided hypotheses, and a difference was con-
`sidered statistically significant when the two-tailed P
`value was 5.05. Efficacy measures were changes in
`mean clinician- and patient—rated nasal symptoms
`(both total and individual nasal symptom scores), and
`frequency of patient- and clinician-scored ratings of
`overall response to treatment. It was estimated that
`150 patients per treatmentarm would provide approx-
`imately 80% power to detect a difference between
`active treatments of at least 30 in mean change from
`baseline in clinician-rated and patient-rated total nasal
`symptom scores at a significance level of
`.05.
`Demographic and baseline disease characteristics of
`patients were summarized by treatment group. The
`chi-square test was performed to compare differences
`
`1 20 The Journal of Family Practice, Vol. 47, No. 2 (Aug), 1998
`
`with respect to sex, ethnic origin, childbearing poten-
`tial, pregnancy status, type of birth control used, and
`clinician- and patient-rated overall evaluations. The
`analysis of variance F test was used to compare differ-
`ences with respect to age, sex, ethnic origin, and indi-
`vidual and total clinician- and patient-rated symptom
`scores. In the RQLQ, descriptive statistics were used
`to evaluate differences among treatment groups for
`baseline scores, and descriptive and inferential statis-
`tics were used to compare the mean change from base-
`line RQLQ scores among and between the four treat-
`ment groups.
`Safety measures included the incidence of poten-
`tially drug-related adverse events. Fisher’s exact test
`was performed on pairs of treatments to detect differ-
`ences in the number of patients with potentially drug—
`related adverse events overall and by body system.
`
`RESULTS
`
`PATIENT CHARACTERISTICS
`Six hundred patients were enrolled in the study, and
`569 (95%) completed it. Eight patients discontinued
`the study because of adverse events, 13 withdrew
`because of lack of efficacy, and seven withdrew for
`other reasons. Demographic characteristics and com-
`
`
`
`
`
`000003
`
`

`

`
`
` .
`MeanScore NO“i
`
`MeanScore
`
`. , ‘ "2
`'--. a.. 'n ..__
`
`
`
`clinician-rated and patient-rated total nasal symptomlscores after 1 and 2 weeks
`
`of therapy for seasonal allergic rhinitis.
`
`Clinician-Rated
`
`P
`atient-Rated
`
`: « x n u u
`-: Loraiadine
`.... ..FP ANS + Loraladine
`-——Placebo
`
`1....
`
`.. . ..
`
`1
`
`1-7
`
`
`
`Treatment Day
`Treatment Day
`
`FP ANS denotes flutlcasone propionate aqueous nasal spray 200 ug daily; loratadine dosage, 10 mg
`once daily.
`*P < .001 versus placebo.
`TP < .001 versus loratadine.
`:tP < .05 versus FP ANS for mean change from baseline.
`
`ASQNE VS ILEJRATADINE IN RHINITIS
`
`pliance rates were similar among the
`treatment
`groups
`(Table
`1).
`Approximately 90% of the patients
`enrolled were recruited from the
`
`offices of primary care physicians or
`were under no medical care for their
`
`rhinitis symptoms. Less than 10% of
`the patients enrolled in the study
`were recruited from the practices of
`allergists who participated in the
`study.
`
`EFFICACY DATA
`Nasal Symptoms Scores. At base-
`line, mean clinician-rated total nasal
`symptom scores were not signifi-
`cantly different between treatment
`groups. At clinic visits after 1 week
`of therapy (day 7), clinician-rated
`total nasal symptom scores were sig-
`nificantly lower (P < .001) in the FP
`ANS and FF ANS plus loratadine
`groups than in the loratadine only or
`placebo groups (Figure 1). At these
`timepoints, loratadine did not differ
`significantly from placebo aqueous
`nasal spray, and the FP ANS plus
`loratadine combination did not dif-
`
`FP ANS
`+ Loratadine*
`FP ANS*
`._.._._____________________________________
`
`150
`
`40.7
`13-80
`
`68 (45)
`82 (55)
`
`17 (78)
`22 (15)
`11 (7)
`
`150
`
`422
`15-78
`
`74 (49)
`76 (51)
`
`120 (80)
`26 (17)
`4(3)
`
`97.8
`97.9
`
`V 98.0
`982
`
`8 (5)
`3 (2)
`0(0)
`4 i 3)
`/\ _r \_,
`1
`f\
`
`5 (3)
`0 ( 0)
`1 (<1)
`2 ( 1)
`2(1)
`
`T r
`
`ratadine dosage is 10 mg once
`
`TABLE 2
`
`gin, childbearing poten-
`birth control used, and
`rerall evaluations. The
`used to compare differ-
`ethnic origin, and indi-
`patient-rated Symptom
`re statistics were used
`treatment groups for
`2 and inferential statis-
`rean change from base-
`retween the four treat-
`
`ie incidence of poten-
`its. Fisher’s exact test
`ments to detect differ-
`
`with potentially drug-
`."lCl by body system.
`
`
`
`CS
`
`lled in the study, and
`patients discontinued
`events, 13 withdrew .
`1 seven withdrew for
`racteristics and com-
`
`Baseline and Mean Change from Baseline at Day 7 and Day 14 for clinician-Rated
`Nasal Symptom Scores
`Placebo
`Score (SE)
`
`Loratadine
`Score (SE)
`
`FP ANS
`Score (SE)
`
`FP ANS + Lor
`Score (SE)
`
`Total symptom
`score
`Baseline
`Day 7
`Day 14
`Blockage
`Baseline
`Day 7
`Day 14
`
`Discharge
`Baseline
`Day 7
`Day 14
`
`itching
`Baseline
`Day 7
`Day 14
`
`Sneezing
`Baseline
`Day 7
`Day 14
`
`302.4 (4.2)
`-71.0 (7.9)
`-102.0 (8.8)
`
`313.3 (4.0)
`-86.1 (8.6)
`—102.0 (9.9)
`
`304.9 (4.6)
`-149.0 (8.2) Ti
`—187.0 (8.5) Ti
`
`77.0 (1.4)
`-14.2 (2.2)
`-20.0 (2.4)
`
`80.2 (1.2)
`-16.8 (2.3)
`-20.0 (2.6)
`
`78.0 (1 .4)
`-32.8 (2.2) ti
`-42.5 (2.3) tr
`
`81.3 (1.2)
`-18.1 (2.1)
`-27.1 (2.5)
`
`85.0 (1.1)
`-20.1 (2.4)
`-26.9 (2.7)
`
`82.8 (1 .2)
`-38.5 (2.5) Ti
`-46.3 (2.6) Ti
`
`76.0 (1.7)
`-19.9 (2.4)
`-28.4 (2.6)
`
`68.1 (1.9)
`-18.9 (2.5)
`-26.6 (2.7)
`
`76.3 (1.6)
`-26.4 (2.5)
`-29.3 (2.8)
`
`71.7 (1.7)
`-22.7 (2.7)
`-26.3 (2.9)
`
`74.4 (1.8)
`-38.6 (2.6) Ti
`-50.0 (2.5) Ti
`
`69.7 (1.8)
`-38.8 (2.6) Ti
`-48 4 (2.6) Ti;
`
`67.8 (2.0)
`-40.1 (2.7)Ti
`-45.7 (2.9)Ti
`
`Total symptom score is the sum of blockage, discharge, itching, and sneezing (maximum total possible
`= 400).
`FP ANS denotes fluticasone propionate aqueous nasal spray; Lor, loratadine; SE, standard error.
`T P <. 05 versus placebo.
`1 P < .05 versus loratadine.
`
`
`from FP ANS monotherapy
`fer
`(Table 2). After 2 weeks of therapy
`(day 14), total nasal symptoms were
`even further reduced in all treatment
`
`groups, with significantly lower
`scores in the FP ANS and FF ANS
`
`plus loratadine groups than in the
`loratadine or placebo groups. Again,
`loratadine did not differ significantly
`from placebo and there was no dif-
`ference between the FP ANS plus
`loratadine combination and FF ANS
`
`monotherapy.
`The data for clinician-rated indi-
`
`Vidual nasal symptoms were similar
`to the total nasal symptom data
`(Table 2). At both the day 7 and day
`14 assessments, scores in the FP
`ANS and FP ‘ANS plus loratadine
`groups were significantly lower (P S
`.05) than loratadine alone and place-
`bo group scores for blockage, dis-
`charge,
`itching,
`and
`sneezing.
`Clinician-rated scores for all individ-
`ual nasal symptoms did not differ
`significantly between the FP ANS
`monotherapy and FP ANS plus
`loratadine combination treatment
`
`groups. Mean total and individual
`
`
`
`
`
`The Journal of Family Practice, Vol. 47, No. 2 (Aug), 1998 1 21
`
`000004
`
`

`

`
`
`TABI
`
`Mean
`Questil
`
`Variabl
`
`Eye sy
`
`(Tl
`
`e33<<%*
`
`From 5
`
`experir
`investi,
`most f:
`were k
`treatm
`
`taxis (
`for all
`
`This is
`
`and qr
`treatm
`dine. 'l
`
`patieni
`ment r
`
`l l
`
`
`
`«—————~.—j~,——:-e—————~r—‘—~«"
`
`_l FIGURE 3
`Patient-rated overall response to therapy after 2 weeks of
`therapy for seasonal allergic rhinitis.
`
`05O
`
`I Significant improvement
`Moderate improvement
`Mild improvement
`3 No change
`'
`I Mildly worse
`_- Moderately worse
`E Significantly worse
`
`-&a100_4,.a__.l_,{i
`
`
`I0(4)OG+_,l___,_A4,_,l...
`
`
`
`PercentofPatients
`
`
`Placebo
`Loratadine
`FP ANS”
`FF ANS + L0"?
`
`FP ANS denotes fluticasone propionate aqueous nasal spray 200 pg
`daily; loratadine dosage. 10 mg once daily.
`*P < .001 versus placebo.
`TP < .001 versus loratadine.
`
`a
`
`Patients’ Overall Evaluation. Overall patient eval-
`uations were in close agreement with overall clinical
`evaluations. FP ANS and FF ANS plus loratadine were
`significantly more effective than placebo or loratadine
`only (P < .00l)(Figure 3), but were not significantly dif-
`ferent from each other. No significant difference was
`observed between the loratadine and placebo treat-
`ment groups.
`
`PATIENT-RATED QUALITY-OF-LIFE
`CHANGES
`
`At baseline, the mean global RQLQ scores and scores
`on each of the seven domains did not differ between or
`among the
`four
`treatment groups
`(Table
`3).
`Significantly greater improvements in mean global
`RQLQ scores from baseline to day 14 were observed in
`the FP ANS treatment group than in the placebo and
`loratadine only treatment groups (P <. 001). There
`were no significant differences in the mean change
`from baseline RQLQ scores between the loratadine
`only and placebo groups. Significantly greater
`improvements were seen in the FP ANS plus loratadine
`group than in either the loratadine only or placebo
`treatment groups (P<.001); however, the RQLQ scores
`did not differ significantly between the FP ANS plus
`loratadine and FF ANS monotherapy groups.
`
`SAFETY DATA
`The incidence and pattern of drug—related adverse
`events did not differ among the treatment groups.
`
`i
`
` FLUTICASONE VS LORATADINE IN RHINITIS
` 2:;..
`
`
`
`¢
`
`
`Placebo
`
`
`Loratadine‘
`FPlANS*l
`
`
`FF ANS + I-<‘>r“*
`
`FP ANS denotes fluticasone propionate aqueous nasal spray 200 ug
`daily; loratadine dosage, 10 mg once daily.
`‘P < .001 versus placebo.
`TP < .001 versus loratadine.
`
`l
`
`‘Clinician-rated overall response to therapy after 2 weeks of
`therapy for seasonal allergic rhinitis.
`
`I Significant improvement
`Moderate improvement
`Mild improvement
`I No change
`I Mildly worse
`Moderately worse
` Significantly worse
`
`50
`
`45
`
`40
`
`35
`
`30
`
`PercentofPatients
`
`25-]
`20
`
`15
`
`nasal symptom scores for the loratadine and placebo
`treatment groups did not differ significantly at either
`the day 7 or day 14 evaluations.
`The pattern of improvement observed in patient-
`rated total nasal symptom scores was similar to that
`reported in the clinician ratings, except that scores in
`the FP ANS plus loratadine combination group were sig-
`nificantly lower than those in the FP ANS monotherapy
`group at the evaluations on days 1 through 7 and days 8
`through 14 (P values .006 and .017, respectively) (Figure
`1). Individual nasal symptom score data generally con-
`formed to a pattern similar to that seen for total nasal
`symptom scores; at days I through 7 and days 8 through
`14, symptom scores in the FP ANS and FP ANS plus
`loratadine treatment groups were significantly lower
`than those in the loratadine only group (P <05) and
`placebo group (P < .001). Individual nasal scores in the
`FP ANS plus loratadine group were significantly lower
`than those reported by patients in the FP ANS monother-
`apy group for nasal blockage, nasal discharge, and
`sneezing at days I through 7 and 8 through 14, and for
`nasal itching at days I through 7.
`
`In the clinician’s
`Clinicians’ Overall Evaluation.
`overall evaluation at day 14, FP ANS and FF ANS plus
`loratadine were equivalent in efficacy and significantly
`more effective than placebo or
`loratadine only
`(P < .001)(Figure 2). No significant difference was
`observed between the loratadine and placebo treat-
`ment groups.
`
`1 22 The Journal of Family Practice, Vol. 47, No. 2 (Aug), 1998
`
`
`
`
`
`000005
`
`

`

`
`
`vs Lomxi'ADINE IN RHINITIS
`
`
`
`Mean Global and Individual Domain Scores on the Rhinoconjunctivitis Quality of Life
`Questionnaire
`
`Variable
`
`Placebo
`score (SE)
`
`Loratadine
`Score (SE)
`
`FP ANS
`Score (SE)
`
`FP ANS +
`Loratadine
`Score (SE)
`
`
`
`
` icantly more effective than
`
`
`loratadine 10 mg once daily
`or placebo. Adding loratadine
`to FP ANS offered no signifi-
`.
`Cant 1mPr0Ve{“ent Over FF
`ANS alone with respect
`to
`clinician ratings, overall clini-
`cal eval
`t‘
`, ov
`ll atie t
`evaluatiua 10“ d er? nlzfatéld
`H °;‘:1_?“ Tia 19
`b_
`quai y o
`1 e.
`e com ina-
`tion was considered more
`effective according to some
`patient ratings. A lack of any
`significant
`differences
`e ween
`an
`bt
`FPANS
`dFPANS
`in combination with lorata-
`
`3y after 2 weeks of
`
` :.:-:
`
`Nsirt
`
`FP ANS + Lor"T
`
`3 nasal spray 200 ug
`
`%__l
`Ierall patient eval—
`lth overall clinical
`1S loratadine were
`sebo or loratadine
`)t significantly dif-
`mt difference was
`nd placebo treat-
`
`-LIFE
`
`scores and scores
`1 differ between or
`
`3).
`(Table
`pups
`in mean global
`were observed in
`1 the placebo and
`P <. 001). There
`the mean change
`an the loratadine
`
`lficantly greater
`JS plus loratadine
`only or placebo
`the RQLQ scores
`the FP ANS plus
`groups.
`
`' G‘ b I
`O 3 300“?
`DayO
`Day 14
`Nasal symptom score
`D33’ 0
`Day M
`Eye Symptom score
`ay
`D
`0
`Day 14
`
`Activmes Score
`Dayg
`Day 14
`f
`I
`bl
`rac (ca pro ems score
`Day 0
`Day 14
`
`P
`
`Sleep 80079
`Day 0
`Dav-4
`EmO((ona( Score
`3ay0
`Jay 14
`other Symptom SCOre§
`DayO
`Day 14
`
`4.0 (0.1)
`-1.3 (0.1)
`
`4-5 (0-1)
`"1'4(O'1)
`
`.
`.
`38(O1
`-1.2 (0-1
`
`4_4 (0.1
`-1.5 (0.1
`
`4.2 (0.1)
`~13 (0.1
`
`3.5 (0.1
`-W0-1>
`
`3.5 (0.1
`-1.3 (0.1
`
`3.6 (0.1
`-1.3 (0.1)
`
`4.1 (0.1)
`-1.3 (0.1)
`
`4-6 (0-1)
`_1'4(O'1)
`
`.
`.
`38(O1)
`-1.3 (0-1)
`
`46 (0.1)
`—1 5 (0.1)
`
`4.5 (0.1)
`-1.3 (0.1)
`
`3.8 (0.1)
`1-2<0-2>
`
`3.5 (0.1)
`~1 1 (0.1)
`
`3.5 (0.1)
`-1.1 (0.1)
`
`4.1 (0.1)
`-2 2 (0.1)ti
`
`4.0(0.1)
`-2 s(0.1)1:r
`
`4-6 (O-j)
`2'5 (O‘ W:
`
`.
`.
`38(O1)
`-19 (0-‘)Ti
`
`4-5 (O-1)
`2'7 <01”:
`
`.
`3801)
`-20 0 ‘lii
`
`44 (0.4)
`-2 3 (0.1)tt
`
`4'4 01)
`«2.5 (0.1)):
`
`4.4 (0.1)
`42.5 (o.‘)1t
`
`)
`3 7 (O.‘
`-211<0-‘W
`
`_ 3 0.‘)
`-2 7(0.1)1:
`
`3 7 0.‘)
`-22<0-‘>1-
`
`3.5 (0.1)
`-1.9 0.1)):
`
`3.4 O 1)
`-2.1 0.1)):
`
`37 (0.1)
`-1
`O.1)Ti
`
`3.5 (0.1)
`-1.9 (O.1)Ti;
`
`FR ANS denotes flutioasone propionate aqueous nasal spray 200 pg once daily; loratadine dosage, 10 mg once
`dai y. SE denotes standard error.
`‘The global score is defined as the mean of the individual domain scores on a scale from 0 (not troubled) to 6
`(ex remely troubled).
`‘(P < .05 versus placebo based on mean Change from baseline.
`1P < .05 versus loratadine based on mean change from baseline.
`§O her symptoms are defined as those not involving the nose or eye (eg, fatigue, irritability, and tiredness).
`l__
`
`From 5% to 8% of the patients in each treatment group
`experienced an event that was considered by the
`investigators to be related to the study therapy. The
`most frequently reported drug-related adverse events
`were blood in the nasal mucus (1% to 2% in active
`treatment groups and 3% in the placebo group), epis-
`taxis (S1% for all treatments), and Xerostomia (S2%
`for all treatments).
`
`This is the first study to evaluate the efficacy, safety,
`and quality of life of patients with rhinitis following
`treatment With FP ANS in combination with lorata-
`
`dine also has been demon-
`strated In the analysis Of
`pharmacoeconomic
`out-
`comes in this same patient
`-
`_
`p‘;1p“1‘9)‘E1,,°n .tgeIf,§rf§S 91,53
`W ere 3 W1
`,
`,
`P “S
`loratadine
`providing
`no
`advantages over FP ANS
`th
`-th
`t t
`3;ii;‘i..-f§?é’dy (::I1eralrle::i;ei:facO—
`tion with treatment, patient-
`perceived effectiveness with
`Symptom relief,
`impact of
`treatment
`on
`patient
`W0I_‘k/5011001
`_
`attend?-Infiey
`patient effectiveness with
`work/school activities, and
`interference of rhinitis symp_
`.
`.
`f
`toms Wlth patlent per Or"
`mance in leisure/recreation
`activities
`f FF ANS
`.
`.
`'
`Th
`_
`e Superllonty 0
`loratadine for treating
`ovei‘
`symptoms was not
`nasal
`unexpected. Four previous double-blind, double-
`duinmy comparative trials have shown that FP ANS
`200 pg once daily, administered to patients with sea-
`sonal allergic rhinitis for 4 weeks, significantly
`reduced nasal symptoms to a greater degree than
`loratadine.“ With the exception of one study,“ these
`clinical trials relied solely on subjective variables to
`assess efficacy. Jordana et al,“ using portable peak
`inspiratory flowmeter measurements as an objective
`variable, found that FP ANS produced significantly
`greater nasal air flow than loratadine, and that this
`coincided with significantly less nasal blockage on
`waking and during the daytime. The effect of lorata-
`dine on nasal airflow has been shown to be the same
`
`g-related’ adverse
`reatment groups.‘ .
`
`dine. The results of this clinical trial indicate that in
`patients with seasonal allergic rhinitis, a 2-week treat-
`ment regimen with FP ANS 200 pg once daily is signif-
`
`as that of terfenadine,“ an antihistamine that has
`proved over a 4-week period to be no more effective
`than aqueous nasal spray placebo and less effective
`
`
`
`The Journal of Family Practice, Vol. 47, No. 2 (Aug), 1998 123
`
`
`
`000006
`
`

`

`FLUTICASONE VS LORATADINE IN RHINITIS
`
`\
`
`than FP ANS in improving nasal airflow. ‘4
`The superior quality-of-life results observed with
`FP ANS over loratadine in this 2-week clinical trial
`were similar
`to those previously reported by
`Mackowiak” in a 4-week clinical trial comparing the
`same FP ANS regimen with astemizole (10 mg daily),
`another nonsedating antihistamine, in patients with sea-
`sonal allergic rhinitis. Mackowiak found that RQLQ
`improvements paralleled improvements in the role—physi—
`cal domain on the Short Form—36 quality—of—life test, which
`he also administered to his patient population.
`To date, loratadine and other oral nonsedative antihist-
`amines have proved no more effective than placebo aque
`ous nasal spray in placebo—controlled studies in which the
`active comparator was an intranasal coIticosteroid,8~‘3"5v2“
`whereas they have demonstrated superior efficacy to
`placebo tablets in placebo—controlled studies in which the
`active comparator has been another oral antihista111ine.Z7"‘°
`This result may be expected, because an intranasal aque-
`ous nasal spray placebo is capable of washing away secre
`tions, inflammatory cells, and mediators.“-32 For this rea-
`son, aqueous nasal spray placebos exert; some therapeutic
`activity and are not true placebos.
`The clinical efficacy and safety of the combined use
`of an intranasal corticosteroid and an oral antihista-
`mine combination have been studied previously in sev-
`eral clinical trials.‘”“'33 In two clinical trials conducted
`
`over 2 to 14 weeks, the addition of recommended regi-
`mens of intranasal beclomethasone dipropionate to
`regimens of terfenadine 60 mg twice daily or astemi-
`zole 10 mg once daily” prompted significant improve-
`ment in nasal symptoms over the respective antihista-
`mine monotherapy regimens. In a 7-day study,
`the
`addition of
`loratadine 10 mg once daily to a
`beclomethasone dipropionate regimen resulted in sig-
`nificantly greater nasal and ocular symptom relief than
`was achievable with beclomethasone dipropionate
`monotherapy.” However, in a 2-week study,” the addi-
`tion of loratadine 10 mg once daily to a regimen of
`intranasal mometasone furoate 200 pg once daily
`failed to provide any significant additional relief of
`total rhinitis symptoms than was attainable with
`mometasone monotherapy. To date, only one other
`clinical trial” has compared combined use of FF ANS
`and an oral antihistamine with FP ANS monotherapy.
`This study, which was conducted over an 8-week peri-
`od in patients with seasonal allergic rhinitis, did not
`use antihistamine monotherapy