1mm i-i bUItNUIiS LinAi-i‘r
`University of Wisconsin
`1305 Linden UR. Madison, Wis,
`MAR 2 5 1985
`
`5370?.!
`
`VOLUME 14 No l 1986
`
`GSK Exhibit 1049 - Page 1 of 9
`
`

`

`International Editorial Board
`
`Harry L Arnold Jr, DM (USA)
`Professor C N Barnard, MD. MMed. MS, PhD, FACS,
`FACC, DSc (Hon Causal, (South Africa)
`Professor Aldo Bertelli. MD (Italy)
`Professor J Bobon. MD (Belgium)
`Joe L Busscy. MD (US/ti
`C i Chappel. DVM PhD (Canada)
`R N Chaudhuri. MD (indie)
`Professor agr Mohamed Chelli (Tunisia)
`Jonathan 0 Cole. MD(USA)
`L K A Dcrban (Ghana!
`J C Devoghcl. MD (Belgium)
`F Vega Dial. MD (Spain)
`Professor W R Fair. MD. FACS (USA)
`Elisabeth Fell, BSc (UK)
`John F Fielding. BSc. MD. MRCP (Ireland)
`J S Fleming, MD. FRCP (UK)
`Celso—Ramon Garcia, MD (USA)
`Professor Dr H H van Geldcren (Holland)
`Professor Viorel Gligore. MD. DSc (Romania)
`Professor Jean Hamburger (France)
`A Henderson, MD, FRCP, FRC Path. FRCPA
`(Australia)
`_
`.
`Professor Vladimir Hudolin (Yugoslavia)
`Professor I Iconomov, MD (Bulgaria)
`Professor Dr S Jablonska, MD (Poland)
`U Jovanovic, MD (Germany)
`V V Kalbian, MD, FRCPi E]. (Cyprus)
`Professor Dr Antal Kaldor. MD (Hungary)
`F Kamunvi, MB, ChB, DPH (Kenya)
`‘
`Professor S Ogua Kayaalp, MD, MS (Turkey)
`Professor N N Kipshidze. MD (USSR)
`‘
`Professor J Knoll. MD (Hungary)
`Professor P Lechat (France)
`Professor Mario Correa Lima, MD (Brazil)
`
`R E Lister, PhD, BSc, FIBiol (UK)
`Professor Dr G Litarczek (Romania)
`F Loza, MD (UAR)
`Professor T Lynch, FRCPI, FRC Psych, DPM
`(Ireland)
`Professor William MacGowan, FRCSI, FACS
`(Ireland)
`Professor Clovis Martins, MD (Brazil)
`V C Medvei, MD, FRCP (UK)
`M H Melmed, BSc, MB, ChB (Cape Town), MRCOG
`(Israel)
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`W S Ogden. MA. MB. BChir, MRCS Eng, LRCP (UK)
`Professor E O Oiurin, FRCSE, FRCS. FMCS (Nigeria)
`Professor J P Payne, MB. ChB Ed. FFA, RCS Eng (UK)
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`meessor Andrew Semple. CBE, VRD, MD. Ch 3. DPH {.U K)
`Tan Seng—Huat. MB BS. FFARCS, FFARACS. AM
`(Singapore)
`H N Shivnpuri. MD ttndia}
`Professor Eugen Spnnar (CSSR)
`Professor P S J Spencer. BPharm. Ph D. FiBiol. MPS (UK)
`Professor Saline Vannas. MD (Finland)
`Professor A Vannotti, MD (Switzerland)
`Tomoji Yanagita, MD (Japan)
`
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`GSK Exhibit 1049 - Page 2 of 9
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`

`

`36
`
`The Journal ofInternational Medical Research
`
`in the control of hay fever
`treatments
`symptoms and so it was of interest to compare
`the effect of terfenadine alone with that of
`fiunisolide and terfenadine. Terfenadine has
`been chosen because of its reported lack of
`sedative effect (Backhouse et al 1982),
`this
`being the major drawback to antihistamine
`therapy.
`The aim of the study was to compare the
`efficacy of fiunisolide plus terfenadine with
`that of terfenadine alone in relieving symptoms
`of hay fever. The incidences of side-effects in
`the two treatment groups were also compared.
`
`treatment as excellent, good, poor, none or
`symptoms worse.
`In addition to the assessment visits, patients
`completed a daily record of the severity of
`sneezing, runny nose, blocked nose and eye
`symptoms.
`Non-parametric statistical tests were used to
`analyze the data. Within—group comparisons
`were made of assessment data with both
`admission and usual severity scores. Between-
`group differences were examined for each
`assessment as well as the changes from admis—
`sion and from usual severity. Symptom scores
`from diary card data were also compared.
`
`Patients and Methods
`
`The study was of single-blind, parallel design
`with ninety—nine patients being randomly
`allocated to receive either terfenadine alone (T)
`or terfenadine plus flunisolide (T + F). The
`dosages were 60 mg terfenadine twice daily
`and two 25 meg sprays flunisolide to each
`nostril
`twice daily. Treatment was started
`before the onset of the pollen season and
`continued for 11 weeks.
`
`Patients gave verbal informed consent to
`enter
`the study and ethical approval was
`obtained. The study conformed with the
`Declaration of Helsinki.
`
`Patients were aged thirteen to sixty-five
`years and had at
`least a 2-year history of
`moderate to severe seasonal allergic rhinitis.
`Patients were excluded from the study if they
`were pregnant or
`lactating,
`if
`they had
`a respiratory tract
`infection or nasal
`abnormalities
`causing obstruction. Also
`excluded were those who had received
`
`systemic steroid therapy within the previous 3
`months or any anti—allergic treatment within
`the previous 2 weeks.
`Patient history was taken at admission and
`the usual severity of hay fever symptoms, in
`previous years, was established. At subsequent
`assessments, after 3, 7 and 11 weeks,
`the
`severity of individual symptoms was recorded
`and an examination of the nasal mucosa was
`made. Sneezing and nose blowing were rated
`as never/seldom (=1), infrequent (=2), fre-
`quent (=3) or very frequent (=4). Runny
`nose, stuffy nose and ocular symptoms were
`rated as none (= 1), mild (= 2), moderate (= 3)
`or severe (=4). At each visit an over—all
`assessment was made,
`rating the effect of
`
`Results
`
`Forty—nine patients were allocated to the
`T + F group and fifty to the T group and the
`groups were well balanced in terms of age, sex,
`diagnosis and disease history (see Table 1).
`Patients had, in previous seasons, been treated
`with a variety of topical and systemic anti-
`allergic treatments.
`Seventy—five patients remained in the study
`for the full 11 weeks. Seventeen patients with—
`drew from the T group; reasons for this were
`poor symptom control (10), headaches (1),
`pregnancy (1), glandular fever (1),
`lack of
`symptoms (2), personal reasons (1),
`lost to
`follow-up (1). Five patients from the T + F
`group withdrew because of poor symptom
`control (2), personal reasons (2) and leaving
`the country (1). There was a significant
`difference between the groups with respect to
`the total numbers of patients withdrawing
`(p< 0-005) and this was largely accounted for
`by the patients who withdrew because of
`inadequate symptom control. Twenty per cent
`of patients withdrew, for this reason, from the
`terfenadine group and 4% from the T + F
`group (p=0-015).
`Local pollen counts, recorded for a 6-week
`period during June and July,
`indicated that
`substantial amounts of pollen were released
`during this time. This period coincided with
`weeks 3 to 9 of the study. Pollen counts are
`shown in Figures 1—4.
`Table 2 shows the mean symptom scores at
`each assessment and the significances of the
`differences between the treatment groups, both
`on direct comparison and when change from
`admission and usual severity are considered.
`
`GSK Exhibit 1049 - Page 4 of 9
`
`

`

`C I Backhouse, VP Firmamore and C W Gosden
`
`37
`
`Table 1
`
`Admission characteristics
`
`49
`
`28
`21
`
`T 5
`
`0
`
`23
`27
`
`35-0i11.0
`
`35-0i14-3
`
`17-Oi9-7
`
`18-5i11-9
`
`41
`9
`
`15
`35
`
`10
`5
`35
`
`4O
`9
`
`18
`31
`
`11
`8
`31
`
`11
`
`Males
`Females
`
`Mean age : s.d. (years)
`
`Mean duration of disease
`: s.d. (years)
`
`Seasonal rhinitis
`Seasonal/perennial rhinitis
`
`Skin test— positive
`— not known
`
`Asthma
`Dermatitis
`No other known allergy
`
`Usual symptom severity
`Mean score 1 s.d.
`'
`— sneezing
`— nose blowing
`— runny nose
`— stuffy nose
`— eye symptoms
`
`
`
`unique.»been);
`
`|+l+|+|+|+
`
`OOOOO;J\'o(50c.h~'d
`
`LBNLQUJW4:6ngl+|+l+l+l+
`
`O—OOO:J-OC-héfi-LI
`
`their most severe at
`A11 symptoms were at
`week 7, when the pollen level was high.
`Symptoms were less severe on all occasions in
`patients
`in the T + F group and these
`differences were statistically significant for all
`nasal symptoms, except for runny nose and
`stuffy nose at week 11. Differences between
`the groups with respect to changes from usual
`severity were significant
`in most
`instances,
`indicating that the combined treatment was
`more effective than terfenadine alone in reduc-
`ing the degree of allergic reaction normally
`experienced.
`as
`response to treatment,
`The over-all
`assessed by both the doctor and the patient
`was statistically significantly greater in the
`T + F group at all three follow—ups. At week
`7, a good or excellent response was achieved
`by 96% patients in the T + F group as com-
`pared to 62% in the T group (p = 0.001).
`
`1—4 show the daily severities of
`Figures
`as assessed by the patients.
`symptoms
`Symptoms were consistently worse for
`patients in the T group and the difference
`between the groups was greatest between days
`20 to 50, (i.e. when the pollen levels rose).
`There was less worsening of symptoms com—
`pared to baseline with regard to all symptoms
`for the T + F group, although this effect was
`more pronounced for nasal symptoms.
`Similar numbers of
`side-effects were
`
`reported in each treatment group. The most
`commonly reported reaction in the T + F
`group was nasal irritation (ten patients), while
`drowsiness was most frequently reported in the‘
`T group (nine patients). Nausea was also 7’
`reported five times in the latter group. Other
`side-effects in both groups were those that
`could be expected with antihistamine therapy.
`Details of side-effects are given in Table 3.
`
`GSK Exhibit 1049 - Page 5 of 9
`
`

`

`38
`
`The Journal ofInternational Medical Research
`
`
`
`
`
`
`
`MeanSymptomScore(0—3)
`
`1.4
`
`M
`
`.- O
`
`.0 m
`
`mx
`
`0 ED
`
`:3
`
`
`
`4
`
`>-
`
`1
`
`,—A
`
`7'"
`
`i1‘
`
`SJ
`
`.<
`
`1
`
`k5
`
`1”
`
`-‘\
`
`7-
`
`\ <
`
`<
`
`g
`
`280
`
`1:)J: O
`
`..I_
`
`..5K3;000
`II0'!OJ0C
`
`
`
`20
`
`30
`
`-300
`
`-280
`‘260
`
`140
`
`
`
`
`
`POLLENCOUNT(grainS/m3)
`
`A
`
`-220 E
`E
`-200 .‘E
`180 3'
`E
`-160 8
`u
`4140 2
`3
`.120
`g)
`
`100
`
`3‘ 80I
`60
`
`4o20
`
`.
`
`10
`(31/5)
`
`20
`(10/6)
`
`30
`(7.0/6)
`
`4o
`(30/6)
`Days of Study
`
`50
`(10/7)
`
`60
`(20/7)
`
`70
`(30/7)
`
`Fig 1 Patient daily assessments Blocked nose
`
`1.4
`
`8 1-2
`|
`
`9
`e
`g 1.0
`E
`9
`E D-S-l
`«T
`C
`$
`_
`2 O E
`
`D 4-.41 I
`
`021W
`
`
`
`1o
`(31/5)
`
`20
`(10/6)
`
`30
`(20/6)
`
`4'3
`(30/5)
`Days ofStudy
`
`56—
`(10/7)
`
`50
`(20/7)
`
`10
`(30/7)
`
`530
`
`Fig 2 Patient daily assessments Sneezing
`
`GSK Exhibit 1049 - Page 6 of 9
`
`

`

`C I Backhouse, VPFinnamore and C W Gosden
`
`39
`
`300
`
`280
`
`-260
`
`
`
`
`
`MeanSymptomScore(0—3)
`
`
`
`
`
`MeanSymptomScore(073)
`
`0
`
`1'0
`(31/5)
`
`
`20
`(10/6)
`
`
`80
`3'0
`40
`50
`60
`?0
`(20/6)
`(30/6)
`(10/7)
`(20/7)
`(30/7)
`Days of Study
`
`Fig 3 Patient daily assessments Runny nose
`
`60
`
`4O
`
`300
`
`280
`
`260
`
`-240
`
`220 n“
`/m
`'200.
`IDS
`
`-180
`
`'160
`
`‘140
`
`120
`
`100
`
`
`
`
`
`POLLENCOUNT(gra
`
`
`
`
`
` I
`
`‘1-4
`
`10
`(31/5)
`
`20
`(10/6)
`
`30
`(20/6)
`
`4O
`(30/6)
`Days of Study
`
`50
`(10/7)
`
`60
`(20/7)
`
`70
`(30/7)
`
`EU
`
`Fig 4 Patient daily assessments Eye symptoms
`
`GSK Exhibit 1049 - Page 7 of 9
`
`14-
`
`12-
`
`1-0-
`
`0.4.
`
`
`
`
`
`CD 0POLLENCOUNT(grains/m3)
`
`1120100
`- 80
`
`02 _‘_
`
`20
`1-2
`
`

`

`40
`
`Table 2
`Symptom severity
`
`The Journal ofInternational Medical Research
`
`
`
`
`Mean score (range 1 — 4) i 5.11.
`Between-group p-values‘
`
`Changefrom
`Changefrom
`T
`T + F
`admission
`usual
`
`
`Sneezing
`Admission
`Week3
`Week 7
`Week 11
`
`Nose blowing
`Admission
`Week3
`Week 7
`Week 11
`
`1-4 i 0-6
`1-4 i 0-6
`1-2 iO-S
`1-7 i0-9
`1-9 i 1-0
`1-4 i 0-8
`
`1-3 i0-6
`l-OiO-Z
`
`I
`
`1-5 i 0-8
`1-8i0-9
`2-3 i 1-1
`1-3 iO-S
`
`‘
`
`1-4 i 0-7
`1-4i0-7
`1-5 iO-8
`l-0i0-2
`
`0-93
`0-001
`0-02
`0-04
`
`0-78
`0-01
`0-001
`0-04
`
`—
`0-002
`0-02
`0-12
`
`—
`0-11
`0-006
`0-15
`
`Runny nose
`—
`0-58
`1-5 i 0-7
`1-5 i 0-8
`Admission
`0-07
`0-04
`l-4 i0-7
`1-8 :0-9
`WeekS
`Week 7
`2-2 i 1-0
`1-6 1 0-8
`0-003
`0-01
`Week 11
`1-4 i0-8
`l-2i0-5
`0-06
`0-03
`
`
`
`Slum nose
`Admission
`1-4 i 0-8
`
`
`Week3
`1-8 i0-9
`Week 7
`2-2 i1-2
`Week 11
`1-3i0-7
`
`1-4 i 07
`l-4i0-7
`1-5 i 0-8
`l-2i0-5
`
`
`
`
`
`Eye symptoms
`Admission
`1-3i0-6
`1-3 i0-6
`Week3
`1-5i0-7
`1-9i1-0
`
`Week7
`1-9i0-8
`2-0i0-9
`
`Weekll
`1-1 i0-3
`1-4i0-8
`
`
`‘ Mann-Whitney U test
`
`
`
`
`
`
`
`
`0-73
`0-05
`0-008
`0-33
`
`—
`0-02
`0-006
`0-28
`
`0-92
`0-22
`0-71
`0-08
`
`—
`0-23
`0-98
`0-18
`
`Discussion and Conclusion
`
`Patients with seasonal allergic rhinitis were
`studied over an 11-week period between May
`and August. Pollen counts measured during
`June and July indicated that the pollen season
`was covered by the time—span of the study.
`Pollen counts were not available earlier than
`the first week in June which coincided with the
`
`first clinical assessment. There was, however, a
`certain amount of disease activity at this stage,
`as many patients were experiencing symptoms
`of allergic rhinitis. The most severe symptoms
`were noted at the second follow-up visit, which
`was consistent with the levels of pollen
`observed. By the final visit, at the end of the
`study, symptoms had subsided and pollen
`levels were presumed to have fallen to insig-
`nificant amounts.
`
`Treatment with terfenadine 60 mg twice
`
`daily was effective in reducing the severity of
`allergic symptoms. The patients who were
`treated with flunisolide in addition to
`
`severe
`terfenadine had significantly less
`symptoms. The difference between the groups
`was apparent at the 3-week assessment but”
`was
`even more pronounced at
`7 weeks,
`indicating that
`combined treatment with
`flunisolide and an antihistamine preparation is
`more effective than the antihistamine alone,
`even when the antigen challenge is at its peak.
`This additive effect can probably be explained
`by the different modes of action of the two
`treatments. Terfenadine acts by blocking the
`histamine receptors,
`thereby reducing the
`inflammation of
`the nasal mucosa which
`results from the action of histamine. It does
`
`not have any effect on other mediators that
`may be involved. The action of flunisolide is
`
`GSK Exhibit 1049 - Page 8 of 9
`
`

`

`C I Backhouse, VP Finnamore and C W Gosden
`
`41
`
`Table 3
`
`Side-effects
`
`
`
`Eeaction
`Number of reactions
`Number of
`related to treatment
`reports
`
`Terfenadine group
`(28 patients reported side-effects)
`
`6
`9
`Drowsiness/tiredness
`1
`5
`Nausea/vomiting
`2 (1 w/d)
`3
`Headache
`1
`2
`Decreased concentration
`1
`1
`Loss of balance
`Depression
`1
`1
`
`Other
`8 (1 w/d)
`0
`
`
`
`
`Total
`
`Terfenadine +flunisolia'e group
`(35 patients reported side-effects)
`Nasal/throat irritation
`Drowsiness/lethargy
`Headache
`Alcohol hangover
`Irritations
`Husky voice
`Dry throat
`Other
`
`29
`
`12
`
`10
`7
`2
`2
`1
`1
`3
`9
`
`8
`6
`1
`2
`1
`1
`2
`0
`
`Total
`
`35
`
`w/d = withdrawn
`
`less well defined, as is that of other topical
`corticosteroids, but these agents are thought to
`act
`in a number of ways to minimize the
`allergic response. They probably have an
`effect on cell membranes and could inhibit the
`
`(Dickson & Cruickshank 1984). This study
`has demonstrated that treatment with both
`flunisolide and terfenadine is more effective in
`
`alleviating most symptoms of hay fever than is
`the antihistamine alone.
`
`production or other vasoactive substances as
`well as histamine.
`Little difference was found between the
`
`treatment groups in the control of ocular
`symptoms.
`It would be expected that
`the
`antihistamine would have a beneficial effect on
`
`the topical steroid
`eye symptoms and that
`would contribute little further to this.
`It is of interest to examine the side-effect
`
`profiles of the two groups. The mild, transient
`nasal irritation with flunisolide is thought to be
`due to the propylene glycol base.
`Other side—effects were those recognized to
`caused by the CNS depression and
`be
`anticholinergic action of antihistamines.
`Flunisolide has been shown to be more effec-
`
`tive than terfenadine in controlling most of the
`symptoms
`of
`seasonal
`allergic
`rhinitis
`
`REFERENCES
`Backhouse C I
`(1979) Intra-nasal flunisolide in the treatment of allergic
`rhinitis in general practice. Current Medical Research
`and Opinion 6, 14
`Backhouse C I, Brewster B S, Lockhart J D F,
`Maneksha S, Purvis C R & Valle-Jones J C
`(1982) Terfenadine in allergic rhinitis. A comparative
`trial of a new antihistamine versus chlorpheniramine and
`placebo. Practitioner 226, 347
`Brown H M, Engler C & English J R
`(1981) A comparative trial of flunisolide and sodium
`cromoglycate nasal sprays in the treatment of seasonal
`allergic rhinitis. Clinical dining]! 1 I. 169
`Dickson D J & Cruickshank J M
`spray and
`(1984) Comparison of
`flunisolide nasal
`terfenadine tablets in hay fever. British Journal of
`Clinical Practice 38, 416
`Langrick A F
`(1984) Comparison of flunisolide and beclomethasone
`dipropionatc
`in
`seasonal
`allergic
`rhinitis. Current
`Medical Research and Opinion 9, 290
`
`GSK Exhibit 1049 - Page 9 of 9
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