The European
`
`Contraception
`
`Reproductive
`Health Care
`
`Volume
`
`Supplement
`
`Published
`
`quarterly
`
`November
`
`1999
`
`lSSN 13625187
`
`ft
`
`cr
`
`new paradigm for low-dose
`oral contraception
`
`The Proceedings of Symposium held at
`the
`5th Congress of the European Society of Contraception
`
`Praguejune 1998
`
`Pahitffs
`
`Ni 2O22JAPTJ
`PTX 037
`
`WC_LP0405202
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2025, Pg. 1
`
`

`
`The European
`
`Journal
`
`of Contraception
`
`and Reproductive Health
`
`Care 1999
`
`Suppi
`
`1725
`
`Cycle control safety and efficacy of
`24-day regimen of gestodene 60 tg/
`ethinylestradiol 15 pg and
`21-day
`regimen of desogestrel
`150 tg/ethinylestradiol 20 jig
`
`Gestodene
`
`Study Group 324
`
`Objective
`
`This multicenter
`
`open-label
`
`efficacy
`
`the cycle control
`
`containing
`
`21-day
`
`regimen of desogestrel
`
`least
`
`18 years of age who had had regular menstrual cycles
`
`for
`
`study was conducted to compare
`and safety of
`24-day regimen of new ultra-low-dose
`oral contraceptive
`gestodene GTD 60 pg/ethinylestradiol
`EE 15 pg and
`DSG 150 pg/EE 20 pg
`Methods
`Healthy women at
`months were
`
`randomly
`assigned
`from 1074 women were
`included in the analyses Overall 65% of cycles
`were normal with GTD/EE
`and 78% with DSG/EE
`The overall
`was 29% with GTD/EE
`spotting
`bleeding occurring in 6% of cycles
`in the GTD/EE
`group The GTD/EE
`0.001
`
`the prior
`
`Results
`
`Data
`
`bleeding and/or
`
`to treatment for six cycles
`
`incidence ofbreakthrough
`and 20% with DSG/EE
`1% of cycles
`
`with absence of
`
`in the DSG/EE
`
`group and
`
`group had
`
`significantly
`
`shorter
`
`length
`
`of bleeding episodes
`
`vs
`
`days
`
`significantly
`
`lower intensity
`
`0.01
`
`and
`
`significantly
`
`shorter
`
`pain
`
`0.03
`
`or vomiting
`
`0.001
`Safety
`in the DSG/
`
`CD
`
`CD
`
`03
`
`C.
`
`CD
`
`CD
`
`C.
`
`-n
`
`Cs
`
`Zr
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`
`3-
`
`CD
`
`CD
`
`CD
`
`CD
`-o
`
`CD
`
`of bleeding
`time for onset of withdrawal bleeding thaji
`the DSG/EE
`group
`profiles for the two treatment groups were similar Significantly more subjects
`EE group withdrew
`because of breast
`and nausea
`One pregnancy
`Conclusions
`
`The
`
`24-day
`
`occurred in each treatment
`group
`regimen of GTD 60 pg/EE 15 pg provided
`good
`with DSG/EE
`safety profile compared
`formulation offers unique advantages
`and safety for oral contraception
`
`0.05
`
`efficacy
`
`This ultra
`
`acceptable
`
`low..dose
`
`cycle
`
`control
`
`and
`
`favorable
`
`in efficacy
`
`RD
`
`Oral contraceptives Desogestrel Gestodene
`
`Ethinylestradiol
`
`INTRODUCTION
`Oral contraceptive OC development
`lowering both
`and progestogen
`
`estrogen
`
`has
`
`focused on
`
`doses
`
`over
`
`have
`
`been
`
`shown to provide effective
`contraception
`with favorable
`and
`low incidence
`
`cycle
`
`control
`
`of
`
`the past 30 years
`
`in an effort
`
`to reduce the
`
`risk of
`
`sideeffects2
`
`complications
`
`while maintaining
`OC products
`efflcacy Low-dose
`GTD 75 pg pIus ethinylestradiol EE 30 pg or 20 pg
`
`contraceptive
`
`containing
`
`gestodene
`
`In an effort to improve
`safety and tolerability further
`while maintaining
`an ultra-lowdose
`efficacy
`formulation of GTD 60 pg and EE 15 pg has
`
`been
`
`Correspondence
`
`Dr
`
`Spielniann
`
`WyethAyerst
`
`Research
`
`80 Ave do President
`
`\Vilson
`
`Paris
`
`92031
`
`France
`
`17
`
`WC_LP 0405203
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2025, Pg. 2
`
`

`
`Gestodene
`
`vs desogest
`
`ye
`
`Geswdene Study Group 324
`
`pills and
`24day regimen of active
`developed with
`days of placebo To ensure that efficacy was maintained
`the number of active
`this lower dose
`days was
`
`pill
`
`at
`
`increased
`
`objective
`
`ovulations
`
`the placebo
`The
`
`develop
`
`from 21 to 24 thereby shortening
`period when most escape
`of this study was to compare
`the cycle control
`safety and efficacy of this 24-day regimen of GTD 60 pg
`and EE 15 pg with those
`of
`regimen of
`21-day
`currently marketed
`DSG 150 pg and EE 20 pg Mercilon
`
`product
`
`that contains
`
`desogestrel
`
`CD
`
`CD
`
`ii
`
`METHODS
`
`This multicenter open-label
`
`randomized
`
`comparative
`
`Drug administration
`
`Women
`
`were
`
`randomly
`
`assigned
`
`to either GTD/EE
`
`from days
`or DSG/EE
`
`to 24 followed by placebo pills
`
`for
`
`days
`
`from days
`
`to 21
`
`followed by
`
`7-day
`
`pill-free interval
`cycles GTD/EE
`
`and DSG/EE
`
`were
`
`Treatment
`
`was
`
`continued
`
`for six
`
`dispensed in 28-
`All women
`
`day and 21-day blister
`
`packs
`
`respectively
`
`began taking
`
`study medication on the first day of naenses
`
`at cycle
`
`In case of missed active
`
`less
`
`than 12
`
`pill
`
`late women were
`
`told to take the missed pill
`
`at once
`
`continue
`
`taking
`
`the remaining pills
`on subsequent days and start
`
`at
`
`the usual
`
`time
`
`the next blister pack
`
`as
`
`-o
`
`CD
`
`CD
`
`CD
`
`CD
`
`study was conducted
`
`at
`
`61
`
`sites
`
`France
`
`Italy the Netherlands
`
`in Europe Belgium
`The
`
`and Switzerland
`
`study was conducted in accordance with the provisions
`ofHelsinki and its amendments The
`
`ofthe Declaration
`
`study protocol was approved
`
`by appropriate
`
`ethics
`
`committees
`
`and written
`
`informed consent
`
`was obtained
`
`from all subjects
`
`before
`
`enrolment
`
`normally indicated If one or more pills were missed
`women were
`
`told to take
`
`the last
`
`for more
`
`than
`
`additional
`
`contraception
`recommended
`
`for
`
`the
`
`missed pill
`
`at once
`
`and
`
`barriers
`
`or spermicides was
`
`remainder of the cycle
`
`Study assessments
`
`Subjects
`
`physical
`
`were obtained at
`
`the prestudy
`and gynecological
`
`screening
`
`visit Complete
`
`examinations
`
`were
`
`Complete medical
`
`obstetric and gynecological
`
`histories
`
`least
`
`18 years old were
`
`eligible if
`
`conducted during the prestudy screening
`
`and
`
`at
`
`the
`
`posttreatment visit Clinical
`
`laboratory
`
`determinations
`
`under
`
`conditions
`
`between
`
`CD
`
`CD
`C-
`
`CD
`
`Healthy women at
`21 to 35 days
`they had had regular menstrual cycles
`preceding months Women who had recently
`
`for the
`
`were
`
`obtained
`
`(cid:224)sting
`
`days
`
`had
`
`an abortion or given birth and were not breast-
`
`15 and 24 of the prestudy screening
`
`cycle
`
`and cycle
`
`feeding were eligible if they had had at
`
`least one normal
`
`Cervical
`
`cytological
`
`smears Papanicolaou
`
`or Bethesda
`
`cycle
`
`before
`
`the start of study medication
`
`There was
`
`system were obtained at prestudy screening
`
`and post
`
`no upper age
`
`ten cigarettes
`
`more cigarettes
`
`limit for women who smoked fewer
`than
`per day but women who smoked ten or
`only if they were
`
`per day were
`
`enrolled
`
`treatment
`
`serum or urine
`
`p-human
`
`chorionic
`
`gonadotropin
`
`days before
`
`pregnancy
`the start of study medication
`
`test was performed within 15
`
`Sitting systolic
`
`younger
`
`than 36 years of age
`
`from the study
`Subjects were excluded
`if there was
`of any thromboembolic or
`
`or presence
`
`history
`
`and diastolic blood
`
`pressures
`
`and body weight
`
`were
`
`measured
`
`at
`
`the prestudy
`
`screening
`
`baseline cycle
`
`and post-treatment
`
`evaluations
`
`clotting
`
`disorder
`
`cardiovascular
`
`or cerebrovascular
`
`Cyclecontrol
`
`analysis
`
`was
`
`performed
`
`to assess
`
`ii
`
`CD
`-C
`
`CD
`
`disease malignancy
`
`that could interfere with the
`
`conduct
`
`or any other medical condition
`of the study
`Also excluded were women with known or suspected
`In addition women were
`
`pregnancy
`
`ineligible for
`
`enrolment
`
`if they were
`Papanicolaou Pap test
`other estrogens
`
`breast-feeding
`
`positive
`
`or had
`result Women who used any
`or other
`or androgens
`
`progestins
`
`menstrual
`
`pattern
`
`irregularities and cycle
`
`characteristics
`
`for the description
`
`of withdrawal bleeding Cycles were
`
`excluded from analysis
`
`if three
`
`consecutive
`
`pills were
`
`missed or
`
`five or more pills were missed at any time
`
`during the cycle Also excluded were
`
`cycles
`
`that were
`
`started
`
`or more days
`
`early Bleeding
`
`episodes
`
`were
`
`reported
`
`on diary cards Cycles were
`
`classified
`
`as normal
`
`as
`
`recommended
`
`in the
`
`as having breakthrough
`
`forms of contraception except
`other concomitant medications
`
`that could
`
`no bleeding
`
`bleeding/spotting or as having
`of cycle
`
`during the entire cycle Analysis
`
`study or any
`interfere with study assessments
`
`were
`
`also ineligible
`
`control
`
`characteristics
`
`also included determination of
`
`for enrolment
`
`cycle
`
`length and
`
`the withdrawal
`
`bleeding episode
`
`18
`
`The European
`
`Journal of Contraception
`
`and Reproductive Health
`
`Care
`
`WC_LP 040 52 04
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2025, Pg. 3
`
`F.
`

`
`Gestodene
`
`vs desogestrel
`
`Gestodene
`
`Study Group 324
`
`length mean intensity
`
`defined
`
`and latent period Spotting was
`as very slight bleeding that required
`no sanitary
`protection whereas
`
`breakthrough
`
`if
`
`bleeding required
`as normal
`sanitary protection
`cycle was classified
`withdrawal bleeding started during the 7-day period
`the last day of active
`intake the withdrawal
`
`ANCOVA with treatment investigator
`factors and
`by investigator
`
`as
`
`and treatment
`
`the screening
`
`value
`
`as
`
`covariate Within-group
`by use of
`
`assessed
`
`paired
`
`changes
`
`from screening were
`
`test All statistical
`
`tests were
`
`two-sided at an alpha
`
`level of0.05
`
`after
`
`pill
`
`bleeding did not extend beyond 11
`days after
`active pill and the rest of the cycle was without spotting
`
`the last
`
`RESULTS
`
`or breakthrough
`
`bleeding
`
`withdrawal bleeding
`
`Study population
`
`episode was defined
`
`as
`
`sequence
`
`of one or more days
`
`-1
`
`CD
`
`ii
`
`CD
`
`of spotting
`
`breakthrough
`
`7day period after
`
`the
`
`bounded
`
`consecutive
`
`bleeding or both during the
`last day of active
`
`intake
`
`pill
`
`treatment
`
`total of 1074 women were
`and took at
`539 GTD/EE
`
`subjects
`
`and
`
`randomly
`
`assigned
`
`to
`
`subjects
`
`least one dose ofstudy medication
`535 DSG/EE
`
`by
`
`non-bleeding
`
`days Bleeding
`
`intensity
`
`was
`
`rated daily and was
`
`classified
`
`by use of
`
`the following scale
`none
`moderate bleeding
`
`bleeding
`
`spotting
`and
`
`light
`
`heavy
`
`bleeding
`The
`
`safety
`
`assessment
`
`was
`
`based
`
`on
`
`signs
`
`or
`
`symptoms
`
`detected
`
`during physical
`
`examinations
`
`and
`
`clinical
`
`evaluations
`
`as well
`
`as
`
`changes
`
`in laboratory
`
`and vital
`
`sign measurements
`
`from prestudy screening
`
`or baseline
`
`evaluations
`
`adverse
`
`-O
`
`CD
`
`Di
`
`CD
`
`All subjects were
`
`included
`
`At baseline the
`
`and safety analyses
`
`comparable with
`
`characteristics
`
`in efficacy
`two groups were
`and clinical
`regard to demographic
`There were no clinically
`between the
`
`Table
`
`differences
`
`important
`two treatment groups
`
`in
`
`menstrual and obstetrical
`
`history-
`
`examination
`the GTD/EE
`
`findings
`
`group
`
`subjects
`
`or gynecological
`total of 475 subjects 88% in
`90% in the
`and
`484
`
`Treatmentemergent
`events were new adverse
`
`events
`
`not present at
`
`screening
`
`or adverse
`
`events
`
`present
`
`at
`
`the
`
`prestudy
`
`screening
`
`that worsened
`
`during treatment
`
`Efficacy
`
`was
`
`assessed
`
`from the
`
`total number of
`
`pregnancies
`
`was
`
`calculated
`
`index
`
`in each treatment group The Pearl
`by use of the following formula total
`number ofpregnancies
`cycles of exposure
`Life-table
`analysis was carried out to assess
`
`1300/total
`
`the cumnula
`
`five termination rates between
`
`treatments
`
`Statistical
`
`analysis
`
`CD
`
`CD
`
`Li
`
`Di
`
`CD
`
`CD
`
`Li
`
`analysis
`
`at
`
`Body mass index kg/m2
`Mean SD
`
`to
`
`status
`
`Table
`
`Baseline demographic and
`of the study population
`
`cinical
`
`characteristics
`
`Characteristic
`
`Age years
`Mean SD
`Range
`
`Weight kg
`Mean SD
`Range
`
`GTD/EE
`
`In
`
`539
`
`DSG/EE
`
`535
`
`27.6 6.7
`1650
`
`27.4 6.6
`174
`
`60.3 10.5
`
`40.4-108.4
`
`59.7 9.6
`40.01 08.0
`
`21.9 3.2
`
`21.9 3.2
`
`Li
`
`Li
`
`CD
`
`C-
`
`CC
`
`An intent-to-treat
`was conducted which
`included all subjects who were
`randomly
`assigned
`treatment
`and
`took
`least one pill Bleeding
`between
`treatment groups
`by the MantelHaenszel
`
`classification was compared
`
`at each
`
`cycle
`
`test Cycle
`
`compared
`
`control characteristics were
`at each cycle by
`of variance ANOVA with treatment
`and treatment by investigator
`the nsodel The 95% confidence
`
`an analysis
`
`investigator
`
`as
`
`factors in
`
`intervals
`
`were
`
`also
`
`Contraceptive
`
`In
`
`Switcher
`
`Recent
`
`user
`
`Former user
`
`Newuser
`
`345 164%
`25 5%
`109 120%
`60111%
`
`325 161%
`25 15%
`106120%
`7915%
`
`Cigarette
`
`smoker In
`
`18935%
`
`19436%
`
`Cigarettes/day
`
`Mean SD
`Range
`
`9.4 6.1
`
`130
`
`9.2 5.4
`125
`
`GTD gestodene
`DSG desogestrel SO standard
`EE ethinylestradiol
`body mess
`index was unknown
`br one subject
`in each
`
`deviation
`
`group
`
`calculated
`
`Fishers exact
`
`test was used for comparisons
`of treatment groups with respect
`events For routine
`adverse
`
`to the incidence of
`
`laboratory
`
`data vital
`
`signs
`
`and body weight comparisons
`
`between treatment
`
`groups were
`
`performed
`
`by analysis
`
`of covariarice
`
`The Esropean
`
`Journal
`
`Conrrsreption
`
`and Reproductive Iiealth
`
`Care
`
`19
`
`WC_LP 040 5205
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2025, Pg. 4
`
`

`
`Gestodene
`
`vs des
`
`ages He
`
`Gestodene
`
`Study Group 324
`
`Table
`
`Reasons
`
`for premature
`
`discontinuation
`
`100
`
`GTD/EEn
`
`539 DSG/EEn
`
`5351
`
`Reason
`
`Subject
`
`request
`
`Other medical
`
`event
`
`Losttofollow-up
`
`Protocol
`
`violation
`
`Other
`
`Total withdrawn
`
`30
`
`11
`
`64
`
`11
`
`18
`
`12
`
`12
`
`51
`
`10
`
`GTD gestodene
`EE ethinylestradiol
`included pregnancy
`for pregnancy
`choice release from study terminated
`
`DSG desogestrel
`
`desire
`
`investigator
`
`by sponsor
`
`GTD/EE
`
`In
`
`2874
`
`DSGfEE
`
`2901
`
`Normal
`
`BTB and/or
`
`SPT
`
`Absence
`
`of
`
`bleeding
`
`in percentage
`
`of
`
`total
`
`classification
`
`Bleeding
`of cycles BTB
`GTD gestodene
`
`bleeding SPT
`breakthrough
`EE ethinylestradiol
`DSG
`
`CD
`
`CD
`
`.2
`
`60
`
`OC
`
`40
`
`20
`
`Figure
`
`number
`
`spotting
`
`DSG/EE
`
`Sixty-four
`
`six cycles
`completed
`group
`12% women in the GTD/EE
`group and
`51 10% women
`in the DSG/EE
`group were
`withdrawn
`prematurely most commonly because of
`
`of treatment
`
`desogestrel
`
`Cycle
`
`control
`
`medical event Table
`
`During
`
`between
`
`difference
`
`The cycle-control
`GTD/EE
`
`157 were
`
`analysis was based on 2874 cycles of
`2901 of DSG/EE
`
`excluded
`
`and
`
`use
`
`cycles
`
`were
`
`the
`
`total
`
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`CD
`
`CD
`
`CD
`
`CD
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`
`CO
`
`CD
`
`the study there was no significant
`treatment groups in the number of subjects
`some form of concomitant
`therapy The
`group 36 subjects
`of contraception was
`than in the GTD/EE
`0.045
`greater
`group 22 subjects Overall
`349 12%
`were
`cycles of GTD/EE
`346 11% cycles of DSG/EE
`and
`total of6l
`subjects missed at
`one pill
`or more pills 31 6%
`group and 30 6% subjects
`
`methods
`
`there
`
`who took
`
`number ofsubjects
`who used
`
`additional
`
`in the DSG/EE
`
`significantly
`
`in which
`
`least
`
`subjects
`
`failed to take
`
`three
`
`in the GTD/EE
`subjects
`the DSG/EE
`
`group
`
`in
`
`Efficacy
`
`One pregnancy occurred in each treatment
`pregnancy in the GTD/EE
`
`group The
`group occurred during
`
`cycle
`
`five
`
`after
`
`cycle
`
`posttreatment
`
`nonconsecutive
`pills were missed during
`The pregnancy in the DSG/EE
`The cumulative
`
`group occurred
`
`termination
`
`rate for
`
`was 0.004 for GTD/EE
`accidental
`pregnancy
`for DSG/EE
`The cumulative
`
`and
`
`termination rates
`
`per
`and 0.308 for DSG/
`
`differences
`
`were
`
`noted between
`
`index was 0.44 for GTD/EE
`
`woman were 0.339 for GTD/EE
`EE no significant
`treatments The Pearl
`for DSG/EE
`
`and
`
`118
`
`excluded Overall
`in the GTD/
`group 78%
`
`cycles was lower
`in the DSG/EE
`
`percentage of normal
`EE group 65% than
`The proportion of normal
`Figure
`from 56% at cycle
`Ito 70% at cycle
`
`increased
`
`cycles
`in the GTD/EE
`
`to 83% at cycle
`
`in
`
`group and from 68% at cycle
`the DSG/EE
`
`group
`
`The incidence
`
`of breakthrough
`in the GTD/EE
`
`than
`
`Absence
`
`group
`of bleeding was
`and in 1% of
`
`was higher
`bleeding/spotting
`in the DSG/EE
`group
`in 6% of cycles with GTD/EE
`reported
`cycles with DSG/EE
`0.001
`alone was 14% in the GTD/EE
`spotting
`11% in the DSG/EE
`
`The incidence
`
`of
`
`group and
`
`group
`Cycledescriptive analysis was based on 2611
`of GTD/EE
`DSG/EE
`
`420 cycles excluded
`
`and 2780
`
`cycles of
`
`239 cycles excluded Withdrawal
`
`bleeding
`
`cycles
`
`episode
`
`length
`
`and
`latent period were
`0.001 reduced with GTD/EE
`at cycles 15 Figure
`DSG/EE
`
`significantly
`
`compared
`
`with
`
`Safety
`
`reported by 398 74% subjects
`Adverse events were
`in the GTD/EE
`group and 367 69% subjects
`but this difference
`group Table
`
`in the
`
`was not
`
`DSG/EE
`
`20
`
`Tb European
`
`Journal of Catraception
`
`arid Reproductive
`
`Rca/i/i
`
`Care
`
`WC_LP 0405206
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2025, Pg. 5
`
`

`
`Gestedene
`
`vs
`
`desogestrel
`
`Gestodene
`
`Study Group 324
`
`CD
`
`-C
`
`CD
`
`CD
`-o
`
`CD
`
`CD
`
`Treatment
`
`cycle
`
`Table
`
`Adverse events
`
`reported
`
`by
`
`5% of subjects
`
`GTD/EEn
`
`539
`
`DSG/EEn
`
`535
`
`Adverse event
`
`Any event
`
`Headache
`
`Amenorrhea
`
`Abdominal
`
`pain
`
`Flusyndrome
`
`Pharyngitis
`
`Breast pain
`
`bysmenorrhea
`
`Metrorrhagia
`
`Nausea
`
`Infection
`
`Asthenia
`
`Pain
`
`Pelvic
`
`pain
`
`Diarrhea
`
`74
`
`31
`
`15
`
`11
`
`11
`
`11
`
`398
`
`166
`
`80
`
`61
`
`61
`
`60
`
`45
`
`41
`
`37
`
`40
`
`32
`
`28
`
`28
`
`25
`
`24
`
`9s
`
`69
`
`30
`
`10
`
`10
`
`367
`
`162
`
`16
`
`56
`
`50
`
`51
`
`57
`
`28
`
`22
`
`42
`
`37
`
`21
`
`17
`
`20
`
`26
`
`GTD gestodene EE ethinylestradiol DSG desogestrel
`
`statistically
`
`significant
`
`The most
`
`event was headache
`
`which
`
`in each
`
`5-
`CD
`
`Di
`
`CD
`
`Di
`
`5-
`
`CD
`
`-C
`
`CD
`
`CD
`
`-CD
`
`CD
`
`Treatment
`
`cycle
`
`Treatment
`
`cycle
`
`GTDJEE
`
`I- DSG/EE
`
`Figure
`
`Withdrawal
`
`bleeding
`
`IWBI
`
`days
`
`for gestodene/ethinylestradiol
`
`episode length
`GTD/
`
`intensity
`
`latent
`
`and
`EE and desogestrel
`DSG/EE
`
`0.002
`
`CD
`
`Di
`
`CD
`
`CD
`
`5-
`
`-C
`
`C-
`CD
`-C
`
`CD
`5i
`CD
`
`C-
`
`-C
`
`CC
`5-
`
`frequent adverse
`occurred in about 30% of
`treatment group Among adverse
`5% of subjects
`in
`the only
`occurring
`0.001 difference
`was
`higher rate of
`in the GTD/EE
`group 15% in subjects
`than in the DSG/EE
`
`subjects
`
`events
`
`significant
`
`anienorrhea
`
`with at
`
`least
`
`one
`
`occurrence
`
`group 3% Although
`was lower in the DSG/EE
`EE group the
`
`treatment
`
`statistical
`
`significance
`
`the incidence
`of metrorrhagia
`group than in the GTD/
`riot reach
`0.06 The incidences
`between
`
`difference
`
`did
`
`comparable
`
`of
`
`the
`
`breast pain and nausea were
`two groups
`To assess
`common adverse
`the OC user
`
`cause
`
`effects of OCs likely to
`to discontinue
`
`use adverse
`
`effects
`
`that were
`to be definitely
`severe or were judged
`related to OC use were examined Those
`
`categories
`
`of
`
`rated
`
`adverse
`
`effects
`
`that were
`
`classified
`
`as severe or definitely
`
`treatmentrelated
`
`in at
`
`least
`
`five subjects
`
`in either
`
`treatment
`
`group were
`
`identified
`
`Seven
`
`categories
`criteria as shown in Table
`
`of adverse
`
`events met
`
`these
`
`Four of these
`
`adverse
`
`events
`
`did not concern menstrual bleeding abdominal
`
`IDSG/EE
`
`at each
`
`cycle
`
`0.001
`
`vs
`
`events
`
`than
`
`subjects
`
`breast pain and headache
`pain nausea
`For these four
`the GTD 60 Jg/EE 15 pg group had less
`half as many
`with
`severe
`or definitely
`
`ihe European
`
`Journal
`
`of Co/lracepriott
`
`neal Reprodurri
`
`or Health Gate
`
`21
`
`WC_LP0405207
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2025, Pg. 6
`
`

`
`Gestodene
`
`vs desogestrel
`
`Gestodene
`
`Study Group 324
`
`Table
`
`Adverse events with at
`
`least
`
`five
`
`subjects
`
`in either
`
`treatment
`
`group
`
`classified
`
`as severe
`
`or definitely
`
`treatment-related
`
`and
`
`the corresponding
`
`number
`
`of discontinuations
`
`for those adverse
`
`events
`
`Numberof
`
`subjects
`
`Severe
`
`Definitely related
`
`Discontinuation
`
`Event
`
`GTD
`
`DSG
`
`GTD
`
`DSG
`
`GTD
`
`DSG
`
`Abdominal pain
`
`Nausea
`
`Breast pain
`
`Headache
`
`Amenorrhea
`
`Metrorrhagia
`
`Dysmenorrhea
`
`p0.38
`
`10
`
`p0.02
`
`0.29
`
`32
`
`28
`
`p0.69
`
`p0.06
`
`p0.73
`
`p1.00
`
`p0.18
`
`p1.00
`
`p0.12
`
`p0.06
`
`12
`
`0.09
`
`0.03
`
`p0.42
`
`p0.18
`
`11
`
`12
`
`50
`
`24
`
`p0.001
`
`p0.06
`
`p0.07
`
`p1.00
`
`p0.14
`
`NA
`
`GTD gestodene DSG desogestrel
`539 DSG 150ig/EE 20 jig
`15ig
`
`Total
`535
`
`Severe events
`
`excluded
`
`number
`
`of subjects
`
`GID 60 ag/ethinylestradiol
`
`IEEI
`
`-.4
`
`CD
`
`CD
`
`Cl
`
`CD
`
`Cl
`
`CD
`
`CD
`
`ii
`
`flu syndrome bronchitis and pharyngitis none of which were
`possibly
`only subjects who discontinued
`because
`treatment
`Discontinuation
`includes
`drug related
`events Subjects may have
`for multiple reasons
`discontinued
`adverse
`
`of
`
`events
`
`as
`
`the DSG 150 pg/
`
`treatmentrelated adverse
`EE 20 pg group Severe abdominal
`pain occurred
`fourusers ofGTD 60 pg/EE l5pgandsevenusersof
`20 pg No user of GTD 60 pg/EE
`DSG 150 j.Lg/EE
`of nausea
`15 pg discontinued treatment because
`
`in
`
`or
`
`breast
`
`and
`pain compared with four
`five users
`of DSG 150 pgiEE 20 pg Two subjects
`discontinued OC use because
`of
`
`group
`
`respectively
`
`in each
`
`difficult
`
`adverse
`
`effect
`
`to evaluate
`
`for causation
`
`it
`
`for
`
`because
`the most nonspecific OC effects
`is one of
`example only 4% of headaches
`in the study were
`
`classified
`
`by the investigator
`
`as definitely
`
`treatment
`
`related
`
`Three
`
`categories
`
`of adverse
`
`events
`
`concerning
`
`menstrual
`
`bleeding
`
`occurred in five
`
`or more
`
`subjects
`
`in
`
`either
`
`treatment
`
`group and were
`
`classified
`
`as severe or
`
`abdominal
`
`pain
`
`definitely
`
`There was no appreciable
`
`difference
`
`between
`
`groups
`
`and
`
`dysmenorrhea
`
`treatmentrelated amenorrhea metrorrhagia
`The percentage of subjects with
`amenorrhea in the GTD 60 pg/EE 15
`
`classified
`
`as definitely
`
`headaches
`of subjects with severe
`in the percentage
`but the GTD 60 pg/BE 15 pg group had slightly fewer
`headaches
`treatmentrelated
`than the DSG 150 pg/BE 20 pg group
`There were more discontinuations
`due to headache
`the DSG 150 pg/BE 20 pg group
`GTD 60 pg/BE
`15 pg group
`
`in
`
`than
`
`in the
`
`Headache
`
`is
`
`treatmentrelated
`
`pg group was approximately five-fold
`in the DSG 150 pg/BE 20 pg group However
`the two OCs in
`between
`OC use
`
`study there was no difference
`the number of subjects who discontinued
`
`in this
`
`for
`
`greater
`
`than
`
`that
`
`this reason two subjects
`
`in each group There was about
`
`twofold higher
`
`rate of severe or definitely
`
`treatment
`
`Cl
`
`CD
`
`CD
`
`CD
`
`CD
`
`Cl
`
`22
`
`The European
`
`Journal
`
`Contraception
`
`and Reproductive
`
`health
`
`Care
`
`WC_LP 0405208
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2025, Pg. 7
`
`

`
`Gestodene
`
`vs
`
`desogestrel
`
`Gestodene
`
`Study Group 324
`
`related cases ofnietrorrhagia
`
`in the GTD 60 jig/BE
`group There was little difference
`between
`
`15 jig
`
`the groups
`
`for either
`
`of
`
`the
`
`adverse
`
`event
`
`classifications
`
`dysmenorrhea
`
`and
`
`there were no discontinuations
`
`of
`
`for
`
`this reason
`
`total of 30 6% subjects
`in the GTD/EE
`18 3% subjects
`in the DSG/EE
`group were
`from the study for other medical events
`
`group
`
`and
`
`withdrawn
`
`There were
`
`no clinically important changes
`
`for either
`
`treatment group
`
`in routine laboratory
`
`test
`
`values
`
`smear results physical
`
`cervical
`
`blood
`
`pressure
`
`deaths
`
`occurred
`
`examination
`
`findings or
`and body weight measurements
`No
`during the study and no serious or
`
`in BE dose between GTD 60 jig/EB 15 pg and DSG
`150 pg/BE 20 pg or because of reduced eridogenous
`production with the 24-day GTD 60 jig/EB
`The reduced estrogen
`15 pg regimen
`production is
`
`estrogen
`
`due
`
`ovarian
`
`to the high degree and
`blockade
`activity by GTD 60 jig/BE 15 jig particularly
`during the pillfree interval
`
`consistent
`
`of
`
`Similarly
`
`greater
`
`ovarian
`
`the lower incidence
`
`could explain
`suppression
`of abdominal pain with the 24-
`day GTD 60 jig/EE 15 jig regimen Abdominal pain
`in this population may have multiple
`etiologies but one
`of the most common is
`
`the presence of ovarian
`
`cysts or
`
`enlarged
`
`follicles These
`
`conditions
`
`occur
`
`potentially
`
`serious
`
`events
`
`ovarian
`
`3-
`CD
`
`mu
`
`CD
`
`cm
`
`mu
`
`CD
`
`ii
`
`CD
`
`CD
`
`related to study medication
`
`were observed
`
`ES CUS
`
`EON
`
`In the present
`
`study GTD/EB
`
`provided
`
`safety
`
`and
`
`commonly occurs
`
`only pills Thus
`
`unrupturcd
`
`follicles
`
`activity
`
`unruptured
`more often when variable
`is present as
`in lower-dose OCs and progestin
`lower incidence of ovarian
`cysts and
`for users of GTD 60 jig/BE 15 jig
`would be consistent with the finding ofa substantially
`lower incidence
`of severe or definitely
`
`treatmentrelated
`
`efficacy
`
`that was comparable to that with
`
`abdominal pain Decreased
`
`dysmenorrhea
`
`related to
`menstrual flow may also have contributed
`to this lower incidence of abdominal pain
`The
`the GTD/EE
`of
`
`decreased
`
`present 24-day
`
`regimen
`
`product
`
`is
`
`the first
`
`to use
`
`shorter pillfree
`
`interval
`
`One theoretical
`
`benefit of the longerdose
`that more consistent
`concentrations
`
`plasma
`
`regimen
`
`is
`
`of
`
`contraceptive
`the DSG/BE
`
`formulation
`
`the
`
`As was expected
`cycles was lower in the GTD/EE
`lower
`group owing to the
`
`incidence
`
`of normal
`
`progestin
`
`and
`
`estrogen
`
`content The main cycle-control
`
`difference
`
`between
`
`the
`
`groups was
`
`somewhat
`
`bleeding
`
`and
`
`spotting
`
`incidence
`
`higher
`ofbreakthrough
`in women who used GTD/E.E
`
`was more
`
`in
`
`estradiol
`
`bleeding
`
`frequent
`
`progestogen
`
`and
`
`Cu
`
`mu
`
`mu
`
`CD
`
`CD
`
`mu
`
`Absence of withdrawal
`the GTD/EE
`
`group importantly however
`
`there was
`
`no difference
`
`between
`
`treatment
`
`groups in the rate of
`study withdrawal due to lack of bleeding The higher
`rate of absence of withdrawal bleeding with GTD/EE
`was not unexpected
`
`because of the use oflower
`
`steroid
`
`doses
`
`and
`
`24day
`
`rather
`
`than
`
`21day active
`
`pill
`
`regimen
`
`Reassurance
`
`of the two treatments
`
`cycle without bleeding
`
`the majority of subjects
`
`about
`
`the contraceptive
`
`efficacy
`
`as
`
`as well
`the low frequency of
`in most women may explain why
`did not consider
`cycle without
`
`bleeding
`
`to be troublesome
`
`These
`
`cycle
`
`characteristics
`
`both endogenous and
`The reduced
`
`in
`
`lower
`
`exogenous
`
`are maintained
`
`estrogen
`
`effects
`
`implications
`
`variability of
`levels may result
`rate of adverse
`These
`differences may have
`important
`for improving compliance in women who
`take OCs therefore further
`The estrogen
`BE preparation
`
`studies
`
`are warranted
`
`and progestogen
`used in the present
`of any currently
`
`available
`
`doses
`
`in the GTD/
`
`study are lower than
`OC
`
`combination
`
`those
`
`product
`
`It
`
`that
`
`lowering
`
`concentrations
`
`in
`
`is widely acknowledged
`and
`estrogen
`progestogen
`combination OCs has produced
`
`progressive
`
`reductions
`
`cerebrovascular
`
`and
`
`progestogen
`lower incidence
`
`of
`
`typically associated
`
`with
`
`nausea
`
`benefits
`
`in cardiovascular
`and thromboembolic
`risks Additionally lower estrogen
`doses may also be associated with
`common
`sideeffects
`combination OCs such
`as some types of headache
`and breast pain Larger long-term epidemiologic
`study will be
`to verify these projected
`necessary
`for 15 and 20 pg BE preparations
`Extensive
`
`produced
`
`bleeding pattern
`
`that was
`
`acceptable
`
`to
`
`subjects
`
`and not associated with
`
`significantly
`
`different
`
`rate of discontinuation
`
`for
`
`bleeding This
`
`regimen is consistent
`
`irregular
`attribute of the 24-day GTD/EE
`with the marked
`
`degree ofendometrial suppression
`with this formulation3
`
`seen
`
`Nausea
`
`and breast
`
`pain are well known to be related
`
`to estrogen
`
`exposure
`
`so
`
`the observed differences
`
`in
`
`severe
`
`or definitely
`
`treatmentrelated
`
`cases
`
`and
`
`mu
`
`mu
`
`CD
`-C
`
`CD
`
`3-
`
`mu
`
`djscontinuatiorss
`
`are consistent
`
`either with the difference
`
`of currently
`
`available
`
`low-dose
`
`combination
`
`1/se European
`
`Journal
`
`vi Contraception
`
`and Reproductire Health Care
`
`23
`
`WC_LP 04
`
`52
`
`residual ovarian
`
`activity
`
`is characteristic
`OCs7
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2025, Pg. 8
`
`

`
`Gestodene
`
`vs
`
`desogestrel
`
`Gestodene
`
`Study Group 324
`
`Therefore the concern
`
`that
`
`further
`
`decreases
`
`in
`
`estrogen
`
`and progestin
`
`doses
`
`used in combination OCs
`
`Belgium
`
`DeBruyn Mechelen Belgium Gerris
`Antwerpen Belgium J.P Nolens Hasselt Belgium
`
`may
`
`lead to decreased
`
`contraceptive
`
`efficacy
`
`is
`
`J.P BlanchŁre
`
`Caen
`
`France
`
`BernardBesnoit
`
`warranted
`GTD/EE
`
`study the Pearl
`Its the present
`was low and when combined
`
`index for
`
`Caen France J.P Bilhaut Caen France
`
`Coudray
`
`with the non-
`
`Caeta France
`
`Guigues Caen France C.Jolly Caen
`
`comparative
`
`study5 yields
`
`Pearl
`
`index of0.24 Other
`
`clinical studies with this formulation confirm its potent
`effects on the suppression
`
`activity
`
`compared
`
`of ovarian
`
`with those of
`
`21-day
`
`regimen
`
`CD
`
`CD
`
`low-dose
`
`24-day
`
`regimen
`
`provided
`
`acceptable
`
`cycle
`
`jig
`
`France
`
`Nguyen Hieu
`
`Amadio MØrignac
`
`France
`
`Dalbos
`
`Maupain Caen France
`Caen France
`Begles France MA De Granvilliers
`Talence
`France
`France C.H De Vedrine
`Devaure Bordeaux
`Begles France M.M Dress Begles France
`Bordeaux France
`Bordeaux
`J.C
`
`AM Kern Bordeaux France
`
`Guibert
`
`France
`
`Levrier Talence
`
`In summary these results demonstrate that an ultra-
`of GTD 60 ig/EE 15
`and
`control good efficacy
`of low-dose OCs
`plasma progesterone and estradiol
`
`favorable
`
`safety
`The more consistent
`
`profile typical
`
`France
`
`Malgouyat
`
`Bordeaux France
`
`Mallet
`
`Bordeaux-Cauderan
`
`France
`
`Marteau Bordeaux
`
`concentrations
`
`offer
`
`for better
`
`tolerability
`
`the potential
`which should
`contribute to improved
`This new preparation containing ultra-
`compliance
`low doses of GTD and EE combined with
`and
`
`reduced
`
`pillfree
`
`interval
`
`offers prescribers
`
`users unique
`
`advantages in efficacy
`higher dose OCs
`
`and safety
`
`compared
`
`to existing
`
`ACKNOWLEDGEMENTS
`
`France
`
`France
`
`Sentenac
`
`Talence
`
`Safisyan Pessac France
`De Boer Drachten
`the Netherlands
`Van Enk Amsterdam the Netherlands O.J.A
`Mattheussens Leiderdorp the Netherlands H.S The
`T.J.D Ypma mmen
`Den Helder
`the Netherlands Rickli Waedenswil Switzerland
`Florek Baden
`Stadlin Zug
`
`the Netherlands
`
`Switzerland
`
`Switzerland
`
`Bitzer Basel Switzerland
`
`Brunclik
`
`ZUrich Switzerland
`
`Gr(cid:252)ter
`
`Luzern Switzerland
`
`Keller Zurich Switzerland
`
`Lurie
`
`Liestal
`
`The Gestodene Study Group 324
`
`Affronti
`
`Switzerland
`
`Pastorelli
`
`Lugano Switzerland
`
`Italy
`
`Ambrosini
`
`Sassari
`
`Italy
`
`Bocci
`
`Switzerland
`
`CD
`
`Di
`
`CD
`
`CD
`
`CD
`
`CD
`CD
`
`CD
`
`CD
`
`CD
`
`Perugia
`
`Mendrisio
`
`Rey
`Sanzeni Chiasso
`
`Torino Italy
`
`Campogrande
`
`Torino Italy
`
`Switzerland
`
`Schtaeitter
`
`Luzern Switzerland
`
`Dodero Lavagna
`
`Italy
`
`Flamigni Bologna Italy
`
`Brincat Malta
`
`Giardina Torino Italy
`
`Litta Padova
`
`Italy
`
`Nappi Napoli
`
`Napoli
`Montemagno
`Italy M.F Robin-Wendeti
`
`Italy
`
`Bordeaux
`
`Massobrio
`
`Meriggi
`
`Torino Italy
`Scarselli Firenze Italy
`Italy C.P Pauwels
`Namur
`
`Verbania
`
`France
`
`Moreels
`
`Ayphassorho Montrouge
`terbeek Belgium
`
`France
`
`REFERENCES
`
`Fotherby
`
`Caldwell
`
`contraception
`
`New progestogens
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`
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`Drugs
`
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`CD
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`
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`
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`
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`Esidocr
`
`Rev 1997
`
`consequences
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`of
`
`and
`
`concepts
`1106
`
`18
`
`15 .tg on endometrial
`histologic findings in healthy
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`3B
`Suppl
`Lewis MA Heinemann
`
`Care
`
`1999
`
`LAJ Spitzer WO Ct al The
`
`use of oral
`
`contraceptives
`
`and
`
`the occurrence
`
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`
`nayocardial
`
`infarction in young women Results from
`
`human
`
`clinical
`
`Gestodene
`
`The
`
`safety
`
`and
`
`24
`
`The European
`
`Journal of Contraception
`
`and Reproducrice Health
`
`Care
`
`WC_LP040521
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2025, Pg. 9
`
`

`
`Gestoderie vs desogest
`
`ref
`
`Gestodene
`
`Study Group 324
`
`contraceptive
`
`efficacy
`
`of
`
`24-day low-dose
`
`oral
`
`contraceptive
`
`regimen
`
`containing
`
`gesrodene
`
`ethinylesu-adiol
`
`Care 1999
`
`Suppl
`
`60 pg and
`15 pg EurJ Coniracept Reprod Health
`915
`
`Sullivan
`
`Furniss
`
`21day and 24-day
`
`containing
`gestodene
`15 pg on ovarian activity
`
`Spona
`
`Elstein
`
`EtFects
`
`of
`
`oral
`
`regimens
`contraceptive
`60 pg and ethinyl estradiol
`Steril 1999 72 11520
`
`Perth
`
`CD
`
`-C
`
`CD
`
`-C
`
`3-
`CD
`
`3-
`Ca
`
`03
`
`I-
`C-
`
`CD
`
`CD
`
`ii
`
`C-
`CD
`
`-ci
`
`CD
`C-
`
`CD
`
`C-
`
`Ca
`3-
`
`The European
`
`Journal
`
`of Contraception
`
`and Reproductive Health Care
`
`23
`
`WC_LP040521
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2025, Pg. 10