Warner Chilcott v. Lupin Ltd., et al.,
`C.A. 11-05048 (JAP) (TJB)
`Warner Chilcott v. Watson Labs.,
`C.A. 12-2928 (JAP) (TJB)
`
`DTX 477
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2008, Pg. 1
`
`

`
` 7KLVPDWHULDOPD\EHSURWHFWHGE\&RS\ULJKWODZ7LWOH86&RGH
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2008, Pg. 2
`
`

`
`Oral contraceptives andfallirle growth '
`
`Teirhmarm et al.
`
`approximately 30 pg per day, but a recently intro-
`duced oral contraceptive has further reduced the
`ethinylestradiol dose to 20 pg per day.
`Results from a large number ofstudies indicate 7
`that reducing the steroid dose in oral contracep-
`tives, together with the introduction of new pro-
`gestogens, has led to a reduction in metabolic
`impact and a decrease in the incidence of serious
`side—effects, particularly thromboembolisrn, stroke
`and myocardial infarction‘. Most clinical studies
`also demonstrate that the low—dose oral contracep-
`tives are not associated with any significant reduc-
`tion in either contraceptive efficacy or cycle
`controlz. There is, however, some clinical evidence
`from studies with oral contraceptive preparations
`containing 20 pg ethinylestradiol combined with
`150 pg desogestrel that cycle control is impaired3,
`a finding that may reflect the decreased estrogen
`dose.
`
`In order to further investigate the effect on
`ovulation inhibition, suppression of ovarian activ-
`ity, cycle control and the incidence of adverse
`events, of reducing the ethinylestradiol dose to
`20 pg per day, a prospective, randomized, clinical
`study has been performed which compared two
`oral contraceptive preparations, one containing
`30 pg ethinylestradiol/ 75 pg gestodene and the
`other 20 pg ethinylestradiol/ 150 pg desogestrel.
`Although the two preparations contained differ-
`ent progestogens, the two progestogens are similar
`with respect to biological activity”, particularly
`antigonadotropic activity. In addition, both pro-
`gestogens have high progestogenic activity, no
`glucocorticoid activity, no antiandrogenic activity
`and a low level of androgenic activity. Because of
`the broad similarity between the two progestogens
`there is a high probability that the findings of this
`study will reflect the difference in ethinylestradiol
`dose and not the difference in progestogen.
`This paper focuses on the effects of the two oral
`contraceptive preparations on ovarian activity.
`Analysis of cycle control data and the incidence of
`adverse events will be reported in a separate com-
`munication.
`
`SUBJECTS AND METHODS
`
`Subjects
`
`Healthy, sexually active women between 19 and
`40 years of age who requested oral contraception
`
`and had a regular cycle (24~36 days) were con-
`sidered for this study. Afier receiving detailed writ—
`ten and verbal information,
`the subjects signed
`informed consent forms. The decision to include
`individual subjects in the study was made on the
`basis ofa gynecological and laboratory examination
`(normal range offasting triglyceride and cholesterol
`levels, plus a negative urinary glucose test). Body
`weight of subjects was not allowed to exceed the
`normal range by more than 20%. Women regularly
`taking long-term medication were excluded from
`the study, as were women who had taken any
`hormonal medication during the previous 8 weeks.
`Smokers were not allowed to participate in the
`study. The generally accepted contraindications for
`oral contraceptives were strictly observed.
`Over a period of 12 months, a total of 500
`women were recruited from the Outpatients
`Department ofthe Torun Hospital for Women in
`Poland. Out of these 500 women, 84 were ex-
`cluded from the investigation because they had
`discontinued the study after randomization but
`before taking the study medication (14 because of
`pregnancy, three because of a desire to become
`pregnant, 15 for personal reasons and 52 because
`they were lost to follow—up). A total of416 women
`were included in the study.
`Screened subjects were randomly assigned to the
`two study groups: group A received a preparation
`containing 21 coated tablets of 30 pg ethinyl—
`estradiol plus 75 pg gestodene and group B
`received a preparation containing 21 coated tablets
`of 20 pg ethinylestradiol plus 150 pg desogestrel.
`
`Study design
`The investigation was designed as a single—center
`prospective randomized study, conducted in the
`Women’s District Hospital, Torun, Poland.
`During a 4-week screening period (control cycle
`1), subjects’ medical. histories were recorded and
`gynecological and laboratory examinations were
`undertaken, in order to establish which subjects
`met the inclusion criteria for the study. After a
`pretreatment phase of one cycle (control cycle 2),
`subjects received the oral contraceptive prepara-
`tions according to a randomization list in chrono-
`logical order, and began the 12-month treatment
`period. Clinical
`investigations were carried out
`between days 18 and 21 in the control cycle 2 and
`in treatment cycles 1, 3, 6, 9 and 12 (Table 1). The
`
`300
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`

`
`Oral contraceptives andfollicle growth
`
`Teiclimarm et al.
`
`Table 1 Study design: all procedures listed were per-
`formed on day 18-21 of the cycle in control cycle 2 and
`all treatment cycles
`
`level, and the total probability of error with the use
`of several
`target variables was estimated by the
`method of Bonferroni—I-lolm.
`
`Control
`
`Treatment
`
`6
`0
`
`Medical history
`Gynecological
`examination
`Randomization
`
`Ultrasonography
`Follow-up visit
`
`e
`
`0
`9
`
`r
`r1
`
`o
`0
`
`0
`
`O
`9
`
`G
`0
`
`0
`
`0
`9
`
`ultrasound investigations were also performed at
`these times and recorded photographically. At each
`visit, bodyweight was recorded and blood pressure
`was measured after the subject had been sitting for
`5 min. Gynecological examinations (including a
`PAP smear) were repeated during cycles 6 and 12.
`Subjects who withdrew from the study before
`completion were not replaced, regardless of the
`reason for withdrawal, and subjects were excluded
`from the control cycle analysis ifthey did not satisfy
`prespecified criteria regarding pill
`taking. The
`study was performed according to the Declaration
`ofl-lelsinki (reviewed version, Hong Kong 1975).
`The proper conduct of the study was ensured by
`the regular visits ofmonitors and plausibility checks
`on the completed study case report forms.
`
`RESULTS
`
`A total of 207 women received the gestodene
`preparation containing 30 ug ethinylestradiol
`(group A) and 209 received the desogestrel pre-
`paration containing 20 pg ethinylestradiol (group
`B). The total number of treatment cycles in group
`A was 2088, and in group B 2051. At baseline, the
`two treatment groups were comparable with re-
`spect
`to age, height, weight, cycle length and
`follicle growth (Table 2). The median age was 26
`years in both groups.
`Of the 416 subjects who entered the study, 48
`(23.2%) in group A and 54 (25.8%) in group B
`discontinued prior
`to completion. Of these
`withdrawals, 18 and 21 respectively, were at—
`tributed to adverse events (Table 3). The primary,
`complaints leading to withdrawal were headache,
`nausea and abdominal pain. Overall, the incidence
`was similar for the two groups, although more
`adverse events were cited in group B, the 20 pg
`
`Table 2 Demographic and anamnestic data at baseline
`(control cycle 2) for group A (30 |,Lg ethinylestradiol/
`75 [Lg gestodene)
`and group B (20 ttg ethinyl-
`estradiol/ 150 pg desogestrel)
`
`Ultrasound examinations
`
`Vaginal ultrasonography was carried out with a
`Sono—Diagnost XP 1550 S (Philips, Hamburg,
`Germany). Mean follicular diameter was calculated
`by averaging the largest transverse and longitudinal
`diameters of all follicles with a mean diameter of
`> 5 mm.
`
`Age < 20 years (n)
`Age 20-24 years (rt)
`Age 25-29 years (rt)
`Age 30-34 years (n)
`Age 35-40 years (Fl)
`Median age (years)
`Range of age (years)
`
`Group A
`(n = 207)
`
`Group B
`(n = 209)
`
`6
`77
`54
`48
`22
`26
`19-39
`
`9
`65
`62
`45
`28
`26
`19-40
`
`Statistical methods
`
`The following statistical procedures were used to
`analyze the study results. The X2 test was used for
`the comparison of the frequency distributions in
`test groups A and B and in subgroups of selected
`subjects; Student’s 2.‘-test for the comparison of
`mean values; and Mann—Whitney U—test for the
`comparison of individual percentage data. A value
`of p = 0.05 was agreed upon as the significance
`
`Mean height (cm) i SD
`Mean Weight (kg) i SD
`
`163 : 6
`57.8 i 7.0
`
`164 i 6
`584 :l: 7.7
`
`Cycle length (days)
`Mean i SD
`
`Range
`Follicle diameter
`Diameter < 10 mm (n)
`Diameter 10-30 m (n)
`Diameter > 30 m (n)
`Missing data (n)
`
`29.2 :: 2.2
`
`29.2 i 2.1
`
`24-36
`
`25-35
`
`109 (52.7%)
`86 (41.5%)
`10 (4.8%)
`2 (1.0%)
`
`105 (50.2%)
`95 (45.5%)
`7 (33%)
`2 (1.0%)
`
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`
`Oral contraceptives andfollicle growth
`
`Teichntann et al.
`
`Table 3 Withdrawal of subjects from the study and
`reasons for discontinuation in group A (30 pg ethinyl—-
`estradiol/75 |.Lg gestodene) and group B (20 pg ethinyl— H
`estradiol/ 150 pg desogestrel)
`
`Group A (rz) Group B (n)
`
`Number ofvolunteers
`
`Subjects enrolled
`Subjects completed
`Subjects discontinued
`Reason for discontinuation
`Adverse events
`
`Desire for pregnancy
`Request ofsubject
`Protocol violation
`Pregnancy
`
`207
`159
`48
`
`18
`
`4
`23
`3
`0
`
`209
`155
`54
`
`21
`
`4
`28
`0
`1
`
`Table 4 Adverse events leading to withdrawal from
`the study of subjects in group A (30 }.Lg ethinyl~
`estradiol/75 ttg gestodene) and in group B (20 tlg
`ethinylestradiol/150 p.g desogestrel)
`
`Headache
`
`Hypertension
`Nausea
`
`Depressive mood
`Abdominal pain
`Vomiting
`lntermenstrual bleeding
`Dizziness
`\Iervousness
`Breast tension
`Pruritus
`
`Group A (rt) Group B (n)
`4
`5
`
`0
`4
`
`2
`4
`1
`4
`0
`0
`2
`0
`
`1
`4
`
`1
`6
`5
`3
`4
`3
`1
`1
`
`1
`1
`Colpitis
`35
`22
`Total number of events
`21
`18
`Total number of women*
`*Some women cited more than one reason for with-
`drawal
`
`ethinylestradiol/ 150 pg desogestrel group (35 ver-
`sus 22). Table 4 gives a breakdown of the adverse
`events reported by the women who withdrew fiom
`the study.
`One subject from group B (20 pg ethinyl—
`estradiol) became pregnant during treatment. No
`evidence of any drug interaction or errors in tablet
`taking was discovered and it was concluded that
`this was a method failure. Throughout the study
`there was no difference between the groups with
`respect to either blood pressure or body weight.
`
`20-
`
`301
`
`Percentageofwomen 10- O
`
`Control
`cycle 2
`
`1
`
`3
`
`6
`
`Cycle
`
`
`
`Figure 1 The percentage ofwomen with fo]licle—like
`structures of mean diameter 10—3O mm in group A
`(clear bar; 30 ug ethinylestradiol/75 Llg gestodene) and
`group B (shaded bar; 20 pg ethinylestradiol/150 pg
`desogestrel) measured in control cycle 2 and treatment
`cycles 1, 3, 6, 9 and 12.
`
`Percentageofwomen
`
`L»:
`
`I
`
`Control
`cycle 2
`
`1
`
`3
`
`6
`
`Cycle
`
`
`
`Figure 2 The percentage ofiwomen with follicle-like
`structures ofmean diameter > 30 mm in group A (clear
`bar; 30 ug ethinylestradiol/75 ug gestodene) and group
`B (shaded bar; 20 pg ethinylestradiol/ 150 ttg deso—
`gestrel) measured in control cycle 2 and treatment cycles
`1, 3, 6, 9 and 12
`
`One woman withdrew from group B due to
`hypertension.
`At baseline (control Cycle 2), the incidences of
`follicle—like structures with a mean diameter of
`10v30 mm and > 30 mm were similar in the two
`
`groups. In group A (30 jig ethinylestradiol), 42.6%
`of Women had follicle—like structures with a mean
`
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`

`
`Oral contraceptives amlfiillicle growth
`
`Teirlmiarm et :11 .
`
`Table 5 The number of women in group A (30 pg ethinylestradi0l/75 [lg gestodene) and in group B (20 [lg
`ethinylestradiol/150 [lg desogestrel) with follicle-like structures (mean diameter of 10-30 mm and > 30 mm) in
`control cycle 2 and treatment cycles 1, 3, 6, 9 and 12
`
`Group A (11)
`Follicle size
`10-30 mm
`
`Follicle size
`> 30 mm
`
`n
`
`84
`197
`Control cycle 2
`20
`193
`Treatment cycle 1
`8
`179
`Treatment cycle 3
`11
`164
`Treatment cycle 6
`12
`157
`Treatment cycle 9
`7
`153
`Treatment cycle 12
`11, number ofwomen with data available for evaluation
`
`10
`4
`4
`2
`4
`2
`
`Group B (n)
`Follicle size
`10-30 mm
`
`Follicle size
`> 30 mm
`
`90
`19
`31
`19
`27
`19
`
`7
`8
`8
`7
`7
`7
`
`:1
`
`198
`197
`176
`161
`150
`149
`
`diameter of 10-30 mm and 5.1% with a mean
`
`diameter > 30 mm. The corresponding figures for
`group B (20 pg ethinylestradiol), were 45.5% and
`3.5%, respectively. During the treatment phase of
`the study, the incidence ofall follicle—like structures
`decreased in both groups, but this decrease was
`more pronounced in group A (Figures 1 and 2). At
`every cycle investigated, the incidences of follicle-
`like structures of10—30 mm and > 30 mm were
`
`significantly greater in group B. The number of
`women with follicle—like structures during the
`study period is shown in Table 5. When the results
`were analyzed for all cycles, follicle—like structures
`with a mean diameter of 10-30 mm were observed
`
`in a total of 9.7% of cycles in group A, compared
`with 19.0% ofcycles in group B, whilst follicle—like
`structures with a mean diameter > 30 mm were
`
`seen in 1.9% of cycles in group A compared with
`5.0% of cycles in group B. These differences were
`statistically significant (p < 0.05).
`No ruptured follicles indicative of escape ovu-
`lation, or persistent cysts that would have required
`invasive diagnostic investigation, were observed at
`any stage in either group.
`
`DISCUSSION
`
`The results from this study demonstrate that com-
`pared with a preparation containing 30 pg ethinyl—
`estradiol plus 75 pg gestodene, use of an oral
`contraceptive containing 20 pg ethinylestradiol
`plus 150 ug desogestrel is associated with a higher
`probability of morphologically detectable ovarian
`activity at the end of the cycle. From ultrasound
`data alone it is not possible to classify follicular
`
`morphology, and therefore, as suggested by Hoog—
`land‘, the structures measured in the study were
`described as follicle—like structures. Whether these
`
`were persistent normal mature follicles or corpora
`lutea—like structures remains unclear. Additionally,
`with respect to the large follicle—like structures of
`diameter > 30 mm observed in control cycle 2, it
`was considered from the ultrasound data to be most
`
`unlikely that these structures represented endo-
`metrioma. Since the incidence of these structures
`
`was similar in the two groups, it was concluded that
`this possibility should not influence the overall
`findings of the study.
`Several authors have already described the
`occurrence ofresidual ovarian activity, on the basis
`of follicle—like structures, which could be detected
`by ultrasound.
`In a randomized, double—blind,
`placebo—controlled study with a triphasic and a
`rnonophasic oral contraceptive preparation, both
`ofwhich contained 30 ug ethinylestradiol, Young
`and co—workers7 found follicle—like structures with
`a diameter > 18 mm in 20-40% of women who
`
`were treated for four cycles (:1 = 48). As one would
`expect, the incidence offollicle—lil<e structures in a
`control group ofwomen not using oral contracep-
`tion was distinctly higher. at over 60% This is in
`agreement with the results from the study reported
`here, where the incidence offollicle—like structures
`> 10 mm in diameter decreased from just under
`50% in control cycle 2, to between 12 and 14% in
`the treatment cycle 1. A number of other investi-
`gators have also observed follicle—like structures by
`vaginal ultrasonography in women using oral con-
`traceptives. Killick and co—workers3 studied 58
`women during spontaneous ovulatory cycles and
`22 of these women over one cycle using oral
`
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`
`Oral contraceptives andfallitlegrowt/1
`
`Teichmarm et al .
`
`contraception. Follicular growth was demonstrated
`during use of the oral contraceptives. In another
`study, Hooglandé described a prospective ultra- 4
`sound investigation involving 56 women including
`ten women who were using an oral contraceptive
`containing gestodene. Again,
`follicular growth
`could be demonstrated to a varying extent
`in
`women taking an oral contraceptive, although no
`cases of ovulation occurred.
`
`The results from the study reported here did not
`demonstrate any ovarian activity which led to
`ovulation, although there was one pregnancy in
`group B (20 pg ethinylestradiol/150 pg deso-
`gestrel) which could not be attributed to user
`failure. The results do, however, indicate a residual
`stock offollicles at the end ofthe cycle. Although
`it is not possible to draw any conclusions about
`ovulation inhibition or the incidence of ovarian
`
`blastomas with the two preparations from the ul-
`trasound data alone, it is reasonable to conclude
`that a higher degree of follicular growth occurs
`towards the end ofthe second halfofthe cycle with
`the preparation containing desogestrel and the
`lower dose ofethinylestradiol. Because of the sim-
`ilar biological activity of the two progestogens it
`would seem reasonable to argue that this difference
`is the result ofthe reduction in ethinylestradiol dose
`from 30 to 20 pg per day.
`A similar finding has been reported by Elomaa
`and co-workers‘’. In this study, which used trans-
`vaginal ultrasound to assess the effect on follicular
`development ofextending the pill-free period from
`7 to 10 days, three oral contraceptives were com-
`pared. Results showed. that in the first treatment
`cycle following a 7-day pill—free period, the mean
`follicle size was significantly greater (p < 0.01) in
`the monophasic desogestrel group (20 pg ethinyl—
`estradiol than in either the monophasic gestodene
`group (30 pg ethinylestradiol) or the triphasic ges-
`todene group (30-40 pg ethinylestradiol).
`The possibility that some of the follicle-like
`structures observed in the study reported here were
`ovarian cysts and not follicles cannot be excluded.
`This is, however, unlikely to influence the findings
`of this study since the incidencerof clinically diag-
`nosed ovarian cysts with a diameter > 30 mm
`during the use ofovulation inhibitors is known to
`be very small. In an American investigation (1976-
`l985) by Grimes and Hughes”, it was demon-
`
`strated that the incidence ofhospital admissions for
`ovarian cysts was 472-572 per 100 000 women
`aged from 15 to 44 years who were using oral
`contraceptives. The question of whether the re-
`duced relative risk of developing ovarian carci-
`noma, as demonstrated in epidemiological studies
`for higher-dosage preparations, also occurs with
`low-dosage preparations, has
`so far not been
`clarified. The increase in proliferative ovarian ac-
`tivity which occurs when follicles are formed,‘ and
`which has been observed in this and other studies
`
`during treatment with an oral contraceptive, makes
`a critical epidemiological examination of this ques-
`tion necessary.
`The estrogen component of the desogestrel-
`containing oral contraceptive investigated in the
`study reported here has been reduced by one-third
`compared with the older desogestrel-containing
`preparation with 30 pg ethinylestradiol. The main-
`tenance of the progestogen dose at 150 pg per day
`may have resulted in a preponderance ofprogeste-
`genie activity at the expense of cycle stability, since
`there is evidence ofinferior cycle control with this
`preparation when compared with an oral contra-
`ceptive containing 30 pg ethinylestradiol3. It is also
`reasonable to assume that a reduction of the
`
`ethinylestradiol dose by 10 pg may be of impor-
`tance with respect to ovarian activity. Although
`there was no evidence of escape ovulation in any
`women in the study reported here, the fact that
`there was a significant increase in the size of the
`follicle-like structures in the group receiving 20 pg
`ethinylestradiol plus the fact that there was also a
`pregnancy in this group, suggests that reduction of
`ethinylestradiol
`dose when
`combined with
`desogestrel may be important. The question of
`whether, in some cases, increased ovarian activity
`during long-term use of this oral contraceptive
`might have clinical consequences requires further
`investigation.
`
`ACKNOWLEDGEMENTS
`
`The authors gratefully acknowledge the excellent
`training and assistance in vaginal ultrasound given
`by Dr R. Osmers and Dr W. Wilke, Department
`of Obstetrics and Gynecology, University of
`Gottingen, Germany.
`
`304
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`

`
`Oral contraceptives andfollicle growth
`
`Teichmann et al.
`
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`WC Ex. 2008, Pg. 8
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2008, Pg. 8