British Journal of Obstetrics
`
`and Gynaecology
`
`VOLUME 86
`1979
`
`DIFor
`
`FRANK
`LOEUFLER
`rM-r 1Do
`
`I-ri
`
`FEN
`D.L3.2ATEN
`
`LSTJ
`STA
`v.z Buir.wcz
`
`RoJ Coiieg of
`Sus Piace 1egent P.r
`
`naeoogits
`NWI 4iG
`
`WC_LP040503
`
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`

`
`British Journal
`
`Apr11
`
`1979
`
`and Gynuecol
`of Obstetrics
`pp 325329
`VoL 86
`
`OgY
`
`TRIAL OF TWO
`DOUBLE-BLIND
`RANDOMIZED
`LOW DOSE COMNED ORAL CONTRACEPTIVES
`
`BY
`
`WALLLB0tJT4DS5 Medical
`
`Research
`
`Administrator
`
`Family Planning Association
`
`London
`
`Vassat Professor
`
`AXW
`
`Department
`
`Research
`
`WIOOINSt
`of Social and Community Medicine
`Oxford University
`
`OffiŁer
`
`Fifty-five
`
`acetate
`
`150
`
`mg norethis
`like number
`
`with
`
`in
`
`less
`
`Summary
`women using Locstrin20 20 pg ethinyl oestradiol and
`have been
`compared
`as an oral contraceptive
`terone
`pg levonorgestrel
`30 pg ethinyl oustradiol and
`using Microgyrson30
`trial Despite the small sample size the main finding in
`double-blind
`randomized
`and is thus
`control
`Loestriu20 provides
`poor cycle
`is clear-cut
`Although there is also
`than hticrogynon30
`as an oral contraceptive
`the
`than Microgynon30
`may be
`
`the trial
`
`acceptable
`
`suggestion
`
`that
`
`Loestrisi2O
`
`less
`
`effective
`
`difference
`
`in the accidental
`
`pregnancy
`
`rates
`
`is not statistically
`
`significant
`
`IN an endeavour to minimize
`oral
`contraception
`steadily reduced
`
`the risks
`
`associated
`
`have
`manufacturers
`the dose of the
`
`with
`
`over
`
`the years
`of
`the pill. Preparations
`component
`first became
`than 50 pg oestrogen
`less
`and
`in 1973
`in the United Kingdom
`available
`the market
`now captured more than half
`1978 per
`Statistics
`Medical
`Most of these low dose
`one
`but
`products
`ethinyl
`pg
`contains
`LoestrinlO
`mg norethis
`in combination
`oestradiol
`the Family Planning
`In 1974
`acetate
`Association EPA was
`the
`to evaluate
`asked
`and acceptability of Loestrin
`use-effectiveness
`to conduct
`decided
`20 Accordingly it was
`
`oestrogcn
`
`containing
`
`have
`
`Intercontinental
`sonal communication
`30
`
`contain
`
`terone
`
`pg oestrogen
`20
`
`only
`
`with
`
`Pi-reent address Margaret bite Centre 27 Mortiner
`Street London WI
`
`Ltd Seacourt
`
`Tower
`
`address Tetecnmpntiflg
`Present
`Westway Oxford
`
`double-blind
`in
`randomized
`multicentre
`which the new product would be compared with
`30 pg ethinyl oestradiol and
`pill containing
`which
`Microgynon.-3O
`150 pg levonorgestrel
`in widespread
`was already
`
`use in family planning
`
`trial
`
`clinics
`
`Mnrstons
`
`clinics
`
`some
`administered
`
`others
`
`rate of
`
`recruitment
`
`clinics
`
`under
`
`by
`
`of
`
`doctor
`
`of the
`
`Seven
`family
`planning
`FPA administration
`to collaborate
`agreed
`Area Health Authorities
`com
`and enrolment
`of patients
`trial
`in the
`1974 Owing
`to the slow
`in November
`menced
`the number
`however
`to 12
`later increased
`was
`participating
`to the two
`At each clinic patients were allocated
`at random Neither
`the clinic
`products
`nor the patients were told the composition
`that both
`they were informed
`but
`involved
`were combined
`
`pills
`the products
`
`oral contraceptives
`
`325
`
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`
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`

`
`326
`
`nouns VESSEY AND WIGGINS
`
`containing
`
`no more
`
`than
`
`50
`
`This information
`
`sg
`oestrogen
`was also given to each patients
`The pills were
`
`general
`
`pre-coded
`unmarked
`
`practitioner
`
`supplied
`
`in
`
`seale4 envelopes
`
`containing
`
`standard
`
`21 day blister packs
`
`had
`
`To be eligible
`volunteers
`for recruitment
`the normal FPA requirements
`to meet all
`for
`see EPA Clinic
`contraceptive
`treatment
`they had
`Handbook
`to be
`in addition
`and of child-bearing
`
`oral
`
`but
`
`aged
`
`16 to 39
`
`potential ii having
`
`iii menstruating
`
`regularly
`
`years
`regular sexual
`intercourse
`iv prepared
`to
`involun
`risk of
`
`of
`
`slight
`
`accept
`
`clinic
`
`the possibility
`and
`tary pregnaacy
`sufficiently
`reliable
`to
`keep monthly diary charts and to return to the
`Women
`who
`were
`lactating
`for follow-up
`or with
`recent
`
`history
`
`of
`
`intermenstrual
`
`or spotting
`bleeding
`from the trial
`
`were
`
`specifically
`
`excluded
`
`history was taken weight
`At the initial visit
`and
`and blood pressure were
`recorded
`gynaeco
`was made Patients
`were
`examination
`logical
`an envelope
`issued
`containing
`three months
`of
`the appropriate
`supply
`how to take
`ii with written instructions about
`on which to
`them and iii with
`diary card
`note the days pills were taken
`and the occurrence
`of any bleeding
`requiring sanitary protection
`sanitary protection
`not
`spotting
`requiring
`Trial participants were advised
`to the standard
`
`pills
`
`or
`
`to
`
`take the pills
`
`on/7
`
`days
`
`off
`
`next
`
`then
`
`with
`
`according
`
`Resuns
`
`The characteristics of
`
`in the two
`
`the subjects
`are summarized in Table
`treatment
`groups
`Although there are some minor differences
`none
`and there is no
`was
`
`approaches
`
`statistical
`
`significance
`
`suggestion
`
`that the randomisation
`
`procedure
`
`in any way unsatisfactory
`shows
`Table
`the net
`
`II
`
`cumulative
`
`discon
`
`tinuation
`
`100 women
`rates
`per
`ordinal months of use computed
`by the standard
`by TiØtze and Lewit 1974
`methods
`described
`Gross discontinuation
`rates were also calculated
`and differences
`in these rates between
`the two
`
`at
`
`selected
`
`treatment
`
`tested
`
`for statistical
`
`were
`groups
`by the log-rank method
`significance
`1977 It can be seen
`from Table
`Azen et
`Loestrin20 discontinued
`that women using
`of abnormal
`treatment
`because
`bleeding
`than women using Micrngynon30
`l0l 00l but
`that
`the rates
`reasons were closely
`similar in the two treatment
`groups Of the 13
`women who stopped
`taking Loestrin20 because
`of abnormal
`complained nf ollgo
`bleeding
`menorrhoea or amenorrhoea while the other
`Of
`
`more often
`y2
`discontinuation
`
`for other
`
`described
`
`by
`
`II
`
`far
`
`of
`
`bleeding
`
`the
`
`of
`complained
`irregular
`women who stopped
`
`taldng Microgynon30
`
`Taar.s
`
`Characteristics
`
`of the subjects
`
`in the
`
`two treatment
`
`groups
`
`on c.drnisston to the
`
`trial
`
`regimen
`
`menstrual
`
`commencing
`and
`
`period
`
`21 days
`on day
`
`of
`
`the
`
`using additional
`
`contra
`
`ceptive
`
`precautions
`
`during
`
`the first
`
`14 days
`
`of
`
`Meanageyears
`
`treatment
`
`Follow-up
`
`visits were
`
`arranged
`
`at
`
`Characteristic
`
`Loestrin-20
`
`tdicrogynon-311
`
`3-monthly intervals
`
`total of 133 patients was recruited between
`November
`1974 and September 1976 Of these
`11 who
`23 have been excluded
`from the analysis
`had
`Loestrin20
`
`taken
`
`or Microgynon30
`who never
`com
`who did
`and
`not
`visit and
`
`their
`
`initial
`
`before
`
`entering
`
`the
`
`trial
`
`menced
`
`taking
`
`their pills
`
`return to the clinic
`
`after
`
`could
`
`not
`
`be
`
`traced
`
`The present
`thus
`report
`of whom 55 were admitted
`110 patients
`concerns
`to each of the two treatment
`of
`groups All but
`group were
`they dis
`
`these subjects
`
`in each
`
`treatment
`
`successfully
`
`followed
`
`either
`
`until
`
`Nulliparous
`
`per cent
`
`Irregular
`
`periods
`
`percent
`
`Ususlcyclelength
`3odsyspercent
`
`Usual
`
`dnration
`
`bleeding
`
`percent
`
`of
`
`days
`
`Usingcombined
`
`pill
`
`as
`
`last contraceptive
`
`percent
`
`Number of subjects
`
`in
`
`continued
`
`the
`
`closure date
`
`trial pill
`1st Decemb(cid:231)r
`
`or up
`1976
`
`to the
`
`study
`
`group
`
`253
`
`45
`
`13
`
`11
`
`65
`
`55
`
`2I
`
`35
`
`i3
`
`20
`
`62
`
`55
`
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`
`tOtJBLE-BLTND ORAL CONThACEPTIVE
`
`TRIAL
`
`327
`
`Net
`
`cwnulutlve
`
`discontinuation
`
`rates per
`
`JOO
`
`women
`
`by reason
`
`ftc discontinuation
`
`at
`
`selected
`
`ordinal months of use
`
`Thail
`
`II
`
`Ordinal months
`
`of use
`
`Reason
`
`for discdntiniiation
`
`Accidental
`
`pregnancy
`
`Abnormalbleeding
`
`Othersideeffects
`
`Plassuingpregnsncy
`
`Otherpersonaireasons
`
`Continuation rate
`
`Woman-months
`
`of use cumulative
`
`Significance
`
`differeslce
`
`of
`
`NS
`
`1t1
`
`0W
`
`NS
`
`14$
`
`145
`
`Treatment
`
`group
`
`Tel
`
`tel
`
`Tel
`
`TA
`
`TA
`
`00
`
`75
`37
`
`129
`93
`
`19
`19
`
`37
`56
`
`72
`794
`
`189
`
`191
`
`12
`
`4-1
`19
`
`270
`37
`
`206
`
`118
`72
`
`10O
`141
`
`27
`524
`
`333
`
`400
`
`41
`19
`
`178
`37
`
`17O
`175
`
`6O
`41
`
`100
`7.6
`
`451
`65-2
`
`288
`
`331
`
`Log rank method
`
`using
`
`gross
`
`rates see Asen er a1 1977
`
`Loestriu-20
`
`Microgynon-30
`
`because
`
`of
`
`disturbances
`
`of
`
`bleeding
`
`complained that bleeding
`that
`was prolonged
`
`other
`
`was irregular
`
`one
`and the
`
`Distribution
`
`of cycle
`
`length
`
`in the
`
`two treatment
`
`groups
`
`TAas.s
`
`iii
`
`terms breakthrough
`
`bleeding
`
`or intermenstrual
`
`bleeding
`
`are inapplicable
`
`On
`
`to our analysis
`of menstrual
`
`the overall distribution
`
`this basis
`cycle length in the two treatment
`is given
`groups
`in Table UI
`few women in each of the groups
`and
`their diary cards properly
`to complete
`to the table but
`The
`
`results
`
`shown
`
`in Table
`
`II
`
`of use
`
`is not
`
`failed
`
`have
`
`this
`
`not contributed
`therefore
`is unlikely to be of any consequence
`in Table
`Ill indicate
`quite clearly
`shown
`that Loestrin20 provides much less satisfactory
`in view
`of
`than Microgynon30
`cycle control
`of discontinuation
`these data the pattern
`of the two products
`
`216
`
`10O0
`
`data
`
`of
`
`groups
`satis
`
`less
`
`Table
`
`trienstrual
`
`Again
`
`factory
`
`associated with
`
`on the duration
`IV provides
`bleeding in the two treatment
`to be
`Loestrin2O appears
`its use
`being
`than Microgynon30
`short up to
`an excess of both
`or more days episodes
`days and prolonged
`the information
`of bleeding TableVsununaxizes
`both
`that occurring
`
`on bleeding
`In analysing
`on the diary cards we defined men
`
`the data
`
`patterns
`
`recorded
`
`strual
`
`bleeding
`
`as
`
`any
`
`bleeding
`
`of
`
`sufficient
`
`Cycle
`length
`days
`
`No of
`
`cycles
`
`irrespec
`severity to require sanitary protection
`on days when tablets
`five of whether
`it occurred
`the
`day tablet-free
`that
`
`were
`
`taken
`
`intervals
`
`or
`
`during
`This of
`
`course
`
`implies
`
`the
`
`Loestrin-20
`
`Microgynon-30
`
`per
`
`cent
`
`217
`
`51
`
`54.4
`40
`
`34.5
`
`No of
`
`cycles
`
`28
`
`10
`
`397
`
`17
`
`459
`
`per
`
`cent
`
`61
`22
`g55
`
`1-5
`
`37
`
`lOOt
`
`17
`
`IS24
`2531
`
`3238
`39
`
`Total
`
`60
`
`14
`
`150
`
`11
`
`41
`
`on
`
`spotting
`
`immediately
`
`surprising
`
`before
`
`or immediately
`
`after menstrual
`
`bleeding
`
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`
`328
`
`nOU1lDS YESSEY AND WIGGINS
`
`nasa
`
`IV
`
`the limited data
`
`available
`
`and
`
`no significant
`occurred
`in either
`
`on body weight
`in either
`
`changes
`
`contraceptive
`
`Dlstrthsttion
`
`of duration
`
`of menstrual
`
`bleeding
`
`in the
`
`two
`
`treatment
`
`groups
`
`Loestrin20
`
`Microgynon-30
`
`blood
`
`pressure
`measurement
`
`group
`
`during
`
`the course of treatment
`
`Duration of
`
`menstrual
`days
`
`bleeding
`
`No of
`
`cycles
`
`per
`
`cent
`
`51-8
`
`399
`76
`
`0-7
`
`No of
`
`cycles
`
`181
`
`258
`
`12
`
`per
`
`cent
`
`40-7
`
`56-3
`
`26
`
`0-4
`
`143
`
`130
`
`21
`
`276
`
`100-0
`
`459
`
`100-0
`
`13
`46
`79
`10
`
`Total
`
`stated that
`
`hours
`
`late
`
`Accidenloipregnancies
`Two women had accidental
`pregnancies while
`the second
`taking Loestrin20 one during
`cycle
`cycle Neither woman
`and one during the.seventh
`to having missed
`any pills but both
`admitted
`they might have taken
`several
`pill
`in which they
`the
`during
`cycle
`Both women carried their
`conceived
`pregnancy
`to term and both gave birth to normal healthy
`infants one male one female
`The woman
`who
`became
`taking Microgynon30
`so during
`She claimed
`to have taken
`
`TasaV
`
`Distribution
`
`of duration
`
`of spotting
`
`in
`
`the
`
`two treatment
`
`groups
`
`cycle
`
`Loestrin20
`
`Micrcgynon30
`
`exactly
`
`in accordance
`
`Number of days
`of spotting
`
`No of
`
`cycles
`
`per
`
`cent
`
`No of
`
`cycles
`
`Linked to menstrual
`
`bleeding
`
`pregnancy
`One
`
`of
`
`analysis
`
`pregnancy
`tests while
`
`per
`
`cent
`
`59-5
`
`pregnant
`
`while
`
`did
`
`the fifth
`
`alt her pills
`The
`with the instructions
`
`12
`
`160
`
`96
`
`20
`
`55-0
`
`14-8
`
`7-2
`
`273
`
`159
`
`27
`
`34-6
`
`5-9
`
`at weeks gestation
`was terminated
`from the
`the 23 women excluded
`to have had an accidental
`is also known
`two positive pregnancy
`proven
`by
`taking Loestrin20 The pregnancy
`the third cycle was not asso
`occurred
`during
`ciated with any irregularity in the taking of pills
`abortion
`to 10
`and ended in spontaneous
`at
`
`Total
`
`276
`
`100-0
`
`459
`
`100-0
`
`weeks
`
`gestation
`
`Unlinkedto menstrual
`
`bleeding
`
`12
`
`244
`
`19
`
`13
`
`88-4
`
`6-9
`47
`
`436
`
`16
`
`95-0
`
`3-5
`
`1-5
`
`Total
`
`276
`
`100-0
`
`459
`
`100-0
`
`and
`
`at other
`that occurring
`spotting Differ
`are small
`of Micro
`
`in favour
`
`groups
`
`linked spotting
`times
`in the cycle unlinked
`between
`ences
`the treatment
`but on balance somewhat
`gynon30
`Wc examined the nature
`the other side
`etc
`nausea
`headache
`effects
`depression
`of Loestrin20 and
`
`of
`
`leading
`
`to discontinuation
`see Table Il but could
`Microgynon30
`between
`of any differences
`no indication
`the one
`groups It may be noted however
`woman who developed
`deep vein thrombosis
`the fourth month of
`the trial did so during
`during
`treatment with Microgynon30 We also analysed
`
`discern
`
`the
`
`that
`
`Dsscusssom
`
`Despite
`
`the
`
`small
`
`is
`
`less
`
`size the main
`sample
`trial seems to be clear-cut
`finding in this clinical
`Loestrin20 provides poor cycle control and as
`than
`result
`acceptable
`contraceptive
`There is also
`Microgynosi30
`Loestrin21 might he less
`gynon30
`hut
`the
`difference
`accidental
`
`effective
`
`that
`suggestion
`than Micro
`between
`the
`
`pregnancy
`
`rates
`
`does
`
`not
`
`reach
`
`statistical
`
`significance
`
`and
`the efficacy
`data about
`Other
`published
`acceptability of Loestrin20 seem to be limited
`1972 This
`described
`by Preston
`to those
`of
`in which
`study
`
`author
`
`reported
`
`the results
`
`of
`
`1218
`
`subjects
`
`receiving
`
`the
`experience
`Loestrin20 who
`followed
`for
`wcrc
`8284 cycles was compared with the experience
`numbers
`of
`subjects
`receiving
`comparable
`
`total of
`
`of
`
`different
`
`oestradiol
`
`dosage
`and
`
`combinations
`
`norethisterone
`
`of
`ethinyl
`acetate While
`
`Loestrin20 was only
`
`little less
`
`effective
`
`than
`
`the pills containing
`
`higher
`
`dosages
`
`of
`
`the con-
`
`WC_LP 04
`
`03
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2019, Pg. 5
`
`

`
`stituent steroids there were striking
`of amenorrhoea
`
`the
`
`frequency
`
`differences
`
`in
`
`and
`
`irregular
`
`in
`
`in
`
`the
`
`there is
`
`armamentaritun
`
`ceptive
`
`uncertain
`
`adverse
`
`effects
`
`DOUBLE-BLIND ORAL CONTRACEPflVE nua
`
`329
`
`Acictcows.enoaaeatrn
`
`and Co for financial
`We thank Parke-Davis
`and
`for supplng Loestrin20 and
`support
`Schering Chemicals Ltd for supplying Micro
`non30 We also thank the doctors
`nurses and
`the participating
`lay staff
`
`clinics
`
`for
`
`their
`
`at
`
`careful supervision
`
`of the study subjects
`
`R.asasswcas
`
`line with
`those
`observed
`bleeding
`1974
`later paper Preston
`present study In
`on the basis
`on efficacy
`the informatiob
`up-dated
`of larger numbers of subjects and cycles
`Whether
`place in the contra
`logical
`for Loestrin20 seems
`the major cardiovascular
`If however
`the use of com
`associated with
`to the
`oestrogen
`that women who
`
`bined
`
`component
`
`pills are attributable
`we rather suspect
`
`30
`to
`cg
`pills containIng
`accept
`are unwilling
`on the grounds of safety would do
`than
`
`oestrogen
`
`better to try
`progestngen-only
`preparation
`an ultra-low oestrogen
`
`to
`
`adopt
`Loestrin20
`
`dose
`
`pill
`
`like
`
`Preston
`1375
`Tierze
`
`and Lewit
`17 121
`Gynecology
`
`P11cc
`
`lvi
`
`Roy
`Azen
`Mishell 12 it 1977 American
`and Gynecology
`128329
`1972 Contraception
`Preston
`1974 Journal
`
`Casagrande
`Jcurnalof Obstetrics
`
`and
`
`17
`
`of Reproductive
`
`Medicine
`
`1974 Clinical
`
`Obstetrics
`
`and
`
`WC_LP0405036
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2019, Pg. 6