U.S. patent application number 14/593449 was filed with the patent office on 2015-06-11 for method for post coital contraception in overweight or obese female subjects using ulipristal acetate.
The applicant listed for this patent is LABORATOIRE HRA PHARMA. Invention is credited to Erin Gainer, Delphine Levy, Henri Camille Mathe, Andre Ulmann.
Application Number | 20150157643 14/593449 |
Document ID | / |
Family ID | 43446975 |
Filed Date | 2015-06-11 |
United States Patent
Application |
20150157643 |
Kind Code |
A1 |
Levy; Delphine ; et
al. |
June 11, 2015 |
METHOD FOR POST COITAL CONTRACEPTION IN OVERWEIGHT OR OBESE FEMALE
SUBJECTS USING ULIPRISTAL ACETATE
Abstract
The invention provides a method for providing post coital
contraception in a female subject, comprising providing the subject
with a therapeutically effective amount of ulipristal acetate,
wherein the female subject is overweight or obese.
Inventors: |
Levy; Delphine; (Paris,
FR) ; Ulmann; Andre; (Paris, FR) ; Mathe;
Henri Camille; (Paris, FR) ; Gainer; Erin;
(Paris, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LABORATOIRE HRA PHARMA |
Paris |
|
FR |
|
|
Family ID: |
43446975 |
Appl. No.: |
14/593449 |
Filed: |
January 9, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13575086 |
Oct 12, 2012 |
8962603 |
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PCT/EP2010/068646 |
Dec 1, 2010 |
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14593449 |
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61300393 |
Feb 1, 2010 |
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Current U.S.
Class: |
514/179 |
Current CPC
Class: |
A61P 15/18 20180101;
A61K 31/57 20130101 |
International
Class: |
A61K 31/57 20060101
A61K031/57 |
Claims
1. A method for providing post coital contraception in a female
subject, comprising providing the subject with a therapeutically
effective amount of ulipristal acetate, wherein the female subject
is overweight or obese.
2. The method of claim 1 wherein the female subject has a body mass
index (BMI) above about 25.
3. The method of claim 1, wherein the female subject has a body
mass index (BMI) between about 25 and about 35.
4. The method of claim 1, wherein the female subject has a body
mass index (BMI) between about 25 and about 30.
5. The method of claim 1, wherein the female subject has a body
mass index (BMI) between about 30 and about 35.
6. The method of claim 1, wherein the female subject has a body
mass index (BMI) above about 35.
7. The method of claim 1, wherein post coital contraception is
provided within about 72 hours after unprotected intercourse.
8. The method of claim 1, wherein post coital contraception is
provided within about 120 hours after unprotected intercourse.
9. The method of claim 1, wherein the post coital contraception is
emergency contraception.
10. The method of claim 1, wherein the ulipristal acetate is
administered in an oral dosage form.
11. The method of claim 10, wherein the oral dosage form is a
tablet.
12. The method of claim 1 wherein the dosage form comprises about
30 mg ulipristal acetate.
Description
[0001] The present invention relates to a method for providing post
coital contraception in a female subject who is overweight or
obese.
BACKGROUND TO THE INVENTION
[0002] Emergency contraception (EC), i.e. contraceptive indicated
for the prevention of pregnancy following unprotected intercourse
or a known or suspected contraceptive failure, is a woman's second
chance for primary prevention of pregnancy.
[0003] For decades, various high-dose estrogen-progestin regimens
have been prescribed by experienced gynecologists for EC, generally
involving the off-label administration of high doses of combined
oral contraceptive pills. It is only in the mid-nineteen-nineties
that dedicated products appeared, following requests from
regulatory agencies and women's groups for properly labelled and
packaged preparations. Initially, dedicated products consisted of
high-dose estrogen-progestin preparations. In 1999, based on WHO
publications of randomized clinical trials demonstrating that 0.75
mg levonorgestrel twice was as effective as combined
estrogen-progestin preparations, HRA Pharma's NorLevo.RTM. became
the first progestin-only EC to be granted a marketing authorization
in Western countries. Since that time, several preparations have
been approved elsewhere in the world (e.g. Plan B.RTM.,
Levonelle.RTM., Postinor.RTM.), and currently the standard of care
for EC within 72 hours of unprotected intercourse is the
administration of 1.5 mg of levonorgestrel, either in a single dose
or in two 0.75 mg doses taken 12-24 hours apart. A number of
countries have granted non-prescription status to these
preparations based on levonorgestrel's well-characterized safety
profile and limited contraindications.
[0004] Although EC with 1.5 mg of levonorgestrel has undoubtedly
contributed to the prevention of unwanted pregnancies, it has its
limitations in terms of efficacy: its efficacy rate drops
significantly with the time elapsed since unprotected intercourse.
Reported pregnancy rates from WHO trials rise from approximately
1.5 to 2.6%, respectively, for intake 0 to 24 hrs as compared to
intake 48-72 hrs after intercourse.
[0005] In addition, for a woman who presents for EC more than 72h
after intercourse, the only available method with a proven efficacy
is the insertion of a copper intra-uterine device (although not
approved or labelled for such use in the United States), although
use is limited by both availability and the need for insertion by a
skilled health-care professional.
[0006] Obesity appears to significantly affect the therapeutic
efficacy of oral contraceptives. For example, Holt et al. 2005
showed that being overweight increased the risk of becoming
pregnant. Edelman et al. (2009) found that compared with woman
having a normal body mass index, obese women had altered
pharmacokinetics including half-life, clearance and time to reach
steady state of the oral contraceptive. Obesity is an epidemic
problem in many countries and especially within the United
States.http://www.contraceptivetechnology.org/Trussell
ContraceptionforObeseWomen.ppt--retrieved Dec. 13, 2009).
Accordingly, there is a growing need to develop effective means of
emergency contraception for obese women.
[0007] Ulipristal acetate (also referred to as CDB-2914, VA2914,
HRP-2000 and RTI 3021-012) is an orally-active selective
progesterone receptor modulator (SPRM) that has been developed for
emergency contraception (EC). Ulipristal acetate inhibits or delays
ovulation in a dose-dependent fashion (Stratton et al, 2000). In a
double-blind non-inferiority trial, ulipristal acetate was shown to
be as efficacious as levonorgestrel for preventing pregnancy when
used within 72 hours of UPI (Creinin et al, 2006). Ulipristal
acetate has been approved in Europe, under trademark EllaOne.RTM.,
for use as an emergency contraceptive.
SUMMARY OF THE INVENTION
[0008] The inventors have now found out that the body mass index
(BMI), used to classify obesity status of a subject, has an impact
on efficacy of ulipristal acetate and levonorgestrel as emergency
contraceptives. However the efficacy of contraception decreases
significantly less with ulipristal acetate than with
levonorgestrel.
[0009] The invention thus provides a method for providing post
coital contraception in a female subject, comprising providing the
subject with a therapeutically effective amount of ulipristal
acetate, wherein the female subject is overweight or obese.
[0010] Preferably the female subject has a body mass index (BMI)
above about 25, in particular between about 25 and about 35, e.g.
between about 25 and about 30. In an embodiment, the female subject
has a body mass index (BMI) above about 30, e.g. between about 30
and about 35.
[0011] Especially, for women overweight or with grade I obesity
(BMI between about 25 and about 35), the risk of pregnancy is
divided by 3 when taking ulipristal acetate versus
levonorgestrel.
LEGEND TO THE FIGURE
[0012] The FIGURE is a graph that shows efficacy of ulipristal
acetate (UPA) vs. levonorgestrel (LNG) as emergency contraception,
according to BMI class (WHO).
DETAILED DESCRIPTION OF THE INVENTION
[0013] Obesity is defined as a condition of abnormal or excessive
accumulation of adipose tissue, to the extent that health may be
impaired. The body mass index (BMI; kg/m.sup.2) provides the most
useful, albeit crude, population-level measure of obesity. Obesity
has also been defined using the WHO classification of the BMI
classes for adults: underweight (<18.5), normal weight (18.5 to
24.99), overweight (25 to 29.99), obese grade I (30 to 34.99),
obese grade II (35 to 39.99), obese grade III and more
(.gtoreq.40). See WHO, Global database on Body Mass Index,
http://apps.who.int/index.jsp?introPage=intor.sub.--3/html.
[0014] The effect of BMI in pooled phase III studies was assessed
by comparing pregnancy rates among sub-groups of the study
populations according to WHO weight classes. Pregnancy rates
increased starting from BMI>25, and for women with a BMI>30,
the 95% CI of the observed pregnancy rate overlapped with the
expected pregnancy rate. A meta-analysis of two comparative studies
showed that efficacy of ulipristal acetate remained constant for
underweight and normal (BMI below 25) and for overweight and obese
grade I (BMI 25-34.99) subjects, whereas it decreased in obese
grade II (BMI 35 and above) subjects. Still, ulipristal acetate was
significantly more effective than levonorgestrel in women with a
BMI>25.
[0015] Ulipristal acetate, formerly known as CDB-2914, designates
within the context of this application 17
.alpha.-acetoxy-11.beta.-[4-N,N-dimethylamino-phenyl)-19-norpregna-
4, 9-diene-3,20-dione, represented by formula I:
##STR00001##
[0016] Ulipristal acetate, and methods for its preparation, are
described e.g., in U.S. Pat. Nos. 4,954,490 ; 5,073,548, and
5,929,262, as well as in international patent applications
WO2004/065405 and WO2004/078709, incorporated herein by
reference.
[0017] Its main metabolite is monodemethylated CDB-2914
(CDB-3877A), that is 17.alpha.-acetoxy-11.beta.-
[4-N-methylamino-phenyl)-19-norpregna-4,9-diene-3,20-dione.
[0018] The subject, who may be also designated by the term
"patient", may be any woman in need of a post coital contraception,
preferably of an emergency contraception.
[0019] Any woman of reproductive age may need post coital
contraception or emergency contraception at some point to avoid an
unintended pregnancy. It is meant to be used in situations of
unprotected intercourse, such as:
[0020] when no contraceptive has been used;
[0021] when there is a contraceptive failure or incorrect use,
including: [0022] condom breakage, slippage, or incorrect use;
[0023] non-compliance with dosage regimen for combined oral
contraceptive pills; [0024] non-compliance with dosage regimen for
progestogen-only pill (minipill); [0025] more than two weeks late
for a progestogen-only contraceptive injection
(depot-medroxyprogesterone acetate or norethisterone enanthate);
[0026] more than seven days late for a combined
estrogen-plus-progestogen monthly injection; [0027] dislodgment,
delay in placing, or early removal of a contraceptive hormonal skin
patch or ring; [0028] dislodgment, breakage, tearing, or early
removal of a diaphragm or cervical cap; [0029] failed coitus
interruptus (e.g., ejaculation in vagina or on external genitalia);
[0030] failure of a spermicide tablet or film to melt before
intercourse; [0031] miscalculation of the periodic abstinence
method or failure to abstain on fertile day of cycle; [0032] IUD
expulsion; or in cases of sexual assault when the woman was not
protected by an effective contraceptive method.
[0033] Preferably post coital contraception is provided within 120
hours, preferably within 72 hours, after unprotected intercourse.
For instance, post coital contraception may be provided more than
about 2, 3, 4 and up to 5 or even 6 days after unprotected
intercourse. Preferably, post coital contraception is provided
within about 75, 80, 90, or 96 hours after unprotected intercourse.
Post coital contraception may be provided up to 120 hours,
preferably about 100, 110, 120 hours after unprotected
intercourse.
[0034] In the present invention post coital contraception most
preferably is an emergency contraception.
[0035] Ulipristal acetate may be administered by any convenient
route, including oral, buccal, parenteral, transdermal, vaginal,
uterine, rectal, etc.
[0036] For a brief review of present methods for drug delivery,
see, Langer, Science 249:1527-1533 (1990), which is incorporated
herein by reference. Methods for preparing administrable compounds
are known or are apparent to those skilled in the art and are
described in more detail in, for example, Remington's
Pharmaceutical Science, 17th ed., Mack Publishing Company, Easton,
Pa. (1985), which is incorporated herein by reference, and which is
hereinafter referred to as "Remington."
[0037] For solid compositions, conventional nontoxic solid carriers
may be used which include, for example, pharmaceutical grades of
mannitol, lactose, starch, magnesium stearate, sodium saccharine,
talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the
like. For oral administration, a pharmaceutically acceptable
nontoxic composition is formed by incorporating any of the normally
employed excipients, such as those carriers previously listed.
[0038] Oral solid dosage forms preferentially arc compressed
tablets or capsules. Compressed tablets may contain any of the
excipients described above which are diluents to increase the bulk
of the ulipristal so that production of a compressed tablet of
practical size is possible. Binders, which are agents which impart
cohesive qualities to powdered materials are also necessary.
Starch, gelatin, sugars such as lactose or dextrose, and natural
and synthetic gums are used. Disintegrants are necessary in the
tablets to facilitate break-up of the tablet. Disintegrants include
starches, clays, celluloses, algins, gums and crosslinked polymers.
Lastly small amounts of materials known as lubricants and glidants
are included in the tablets to prevent adhesion to the tablet
material to surfaces in the manufacturing process and to improve
the flow characteristics of the powder material during manufacture.
Colloidal silicon dioxide is most commonly used as a glidant and
compounds such as talc or stearic acids are most commonly used as
lubricants. Procedures for the production and manufacture of
compressed tablets are well known by those skilled in the art (See
Remington).
[0039] Capsules are solid dosage forms using preferentially either
a hard or soft gelatin shell as a container for the mixture of
ulipristal or a metabolite thereof and inert ingredients.
Procedures for production and manufacture of hard gelatin and soft
elastic capsules are well known in the art (See Remington).
[0040] Buccal forms or devices are also useful, such as those
described in U.S. patent application 20050208129, herein
incorporated by reference. U.S. patent application 20050208129
describes a prolonged release bioadhesive mucosal therapeutic
system containing at least one active principle, with an active
principle dissolution test of more than 70% over 8 hours and to a
method for its preparation. Said bioadhesive therapeutic system
comprises quantities of natural proteins representing at least 50%
by weight of active principle and at least 20% by weight of said
tablet, between 10% and 20% of a hydrophilic polymer, and
compression excipients, and comprising between 4% and 10% of an
alkali metal alkylsulphate to reinforce the local availability of
active principle and between 0.1% and 1% of a monohydrate
sugar.
[0041] For parenteral administration, fluid unit dosage forms are
prepared utilizing the compounds and a sterile vehicle, water being
preferred. Ulipristal acetate, depending on the vehicle and
concentration used, can be either suspended or dissolved in the
vehicle. In preparing solutions the compound can be dissolved in
water for injection and filtered sterilized before filling into a
suitable vial or ampoule and sealing. Advantageously, adjuvants
such as a local anesthetic, preservative and buffering agents can
be dissolved in the vehicle. To enhance the stability, the
composition can be frozen after filling into the vial and the water
removed under vacuum. The dry lyophilized powder is then sealed in
the vial and an accompanying vial of water for injection is
supplied to reconstitute the liquid prior to use. Parenteral
suspensions can be prepared in substantially the same manner except
that the compounds are suspended in the vehicle instead of being
dissolved and sterilization cannot be accomplished by filtration.
The compound can be sterilized by exposure to ethylene oxide before
suspending in the sterile vehicle. Advantageously, a surfactant or
wetting agent is included in the composition to facilitate uniform
distribution of ulipristal acetate.
[0042] Additionally, a suppository can be employed to deliver
ulipristal acetate. The active compound can be incorporated into
any of the known suppository bases by methods known in the art.
Examples of such bases include cocoa butter, polyethylene glycols
(carbowaxes), polyethylene sorbitan monostearate, and mixtures of
these with other compatible materials to modify the melting point
or dissolution rate. These suppositories can weigh from about 1 to
2.5 g.
[0043] Transdermal delivery systems comprising a penetration
enhancer and an occlusive backing are of use to deliver ulipristal
acetate. Examples of penetration enhancers include dimethyl
sulfoxide, dimethyl acetamide and dimethylformamide.
[0044] Systems comprising polymeric devices which slowly release or
slowly erode and release within the body to provide continuous
supplies of ulipristal acetate are also of use. Suitable delivery
systems include subcutaneous devices or implants such as those
routinely used to deliver norgestrienone or progestin R2323 and
other medicaments.
[0045] Ulipristal acetate is preferably in form of an oral dosage,
such as a tablet or a capsule, preferably a tablet.
[0046] In a preferred embodiment, it is provided as pharmaceutical
tablet for oral administration, comprising ulipristal acetate in an
amount of 3 to 18 wt %, together with the following excipients: a
diluent in an amount of 60 to 95 wt %, a binding agent in an amount
of 1 to 10 wt %, croscarmellose sodium in an amount of 1 to 10 wt
%, and magnesium stearate in an amount of 0 to 5 wt %.
[0047] According to preferred embodiments, the composition,
preferably in form of a tablet, comprises 10% wt ulipristal acetate
and is designed to contain from 5 to 50 mg ulipristal acetate,
preferably 10, 20, or 30 mg.
[0048] The diluent may be selected from any pharmaceutically
acceptable agent or combination of agents that increases the bulk
quantity of ulipristal acetate so that production of a compressed
tablet of practical size is possible. In a preferred embodiment,
the diluent is selected from the group consisting of a
monosaccharide, a disaccharide, a derivative polyol of a
monosaccharide and hydrates thereof. The term `derivative polyol of
a monosaccharide` stands for a sugar alcohol such as mannitol,
xylitol or sorbitol. Preferably the diluent is selected from the
group consisting of lactose monohydrate and mannitol. In a most
preferred embodiment, the diluent is lactose monohydrate is an
amount of 65 to 92 wt %, more preferably 70-85 wt %.
[0049] The binding agent, or binder, may be selected from any
pharmaceutically acceptable agent (or combination of agents) which
imparts cohesive qualities to powdered materials. The binding agent
may be selected from starch, gelatin, sugars such as cellulose
derivatives, and natural and synthetic gums may be used.
Advantageously, the binding agent of the tablet is selected from
the group consisting of polymers. The binding agent may be a
natural polymer material such as polysaccharide, or a synthetic
polymer such as a plastic polymer. Preferably, the binding agent is
hydroxypropyl methyl cellulose and/or povidone. In a preferred
embodiment, the binding agent is or comprises povidone, preferably
1.5% to 8.5 wt % of povidone, even more preferably between 3-7 wt
%, most preferably about 5 wt % povidone.
[0050] The tablets preferably comprise croscarmellose sodium.
Croscarmellose sodium is a disintegrant, e.g., facilitates break-up
of the tablet. Croscarmellose sodium may be used alone or in
combination with other disintegrants, preferably alone. It is
preferably present in an amount of 1 to 10 wt %, preferably 1.5 to
8.5 wt %, and more preferably 4.5 to 5.5 wt %, or even more
preferably about 5 wt %.
[0051] In preferred embodiments, the tablets of the present
invention contain magnesium stearate. While magnesium stearate may
be used in combination with other lubricants, it is preferably used
alone, in an amount comprised between 0.5 and 5 wt %.
[0052] Preferably, the tablet according to the present invention
comprises lactose monohydrate as a diluent and povidone as a
binding agent.
[0053] In a more specific embodiment, the tablet comprises:
ulipristal acetate 5 to 15 wt %, lactose monohydrate 71 to 87 wt %,
povidone 4.5 to 5.5 wt %, croscarmellose sodium 4.5 to 5.5 wt % and
magnesium stearate 1 to 4 wt %, where the total percentage adds up
to 100.
[0054] In an even more specific embodiment, the tablet comprises:
ulipristal acetate 10%, lactose monohydrate 79 wt %, povidone 5 wt
%, croscarmellose sodium 5 wt % and magnesium stearate 1 wt %.
[0055] Tablets may be prepared according to techniques known per se
in the art. Suitable methods include direct compression ("dry
blending"), dry granulation followed by compression, and wet
granulation followed by drying and compression. Several methods
include the use of compacting roller technology such as a
chilsonator or drop roller, or molding, casting, or extrusion
technologies. The tablet can be a coated tablet or an uncoated
tablet.
[0056] In the preparation of the tablets, commercial mixtures
comprising diluents and binding agents may be used, such as
Avicel.RTM. (microcristalline cellulose), Starlac.RTM. (lactose
monohydrate 85% with maize starch 15%) or, Ludipress.RTM. (lactose
monohydrate 93% with Povidone 7%).
[0057] In a particular embodiment, a 30 mg ulipristal acetate
tablet may be manufactured as follows. Lactose monohydrate 79 wt %,
ulipristal acetate 10 wt % and povidone 5 wt % are mixed and
purified water is added. This granulation step is followed by a
drying step in an oven at 40.degree. C. Croscarmellose sodium 5 wt
% and magnesium stearate 1 wt % are added for the lubrication step.
The obtained formulation is compressed to get the tablet, which
shows the following formulation (Table 1).
TABLE-US-00001 TABLE 1 30 mg ulipristate acetate tablet: Quantity
for one Quantity for one Ingredients tablet (mg) tablet (wt %)
Ulipristal acetate 30.00 10 Lactose Monohydrate 237.00 79 Povidone
15.00 5 Croscarmellose sodium 15.00 5 Magnesium stearate 3.00 1
Total 300.00 100
[0058] Further ulipristal acetate tablets are provided
hereafter.
TABLE-US-00002 TABLE 2 Other ulipristal acetate tablet
formulations: 10 mg tablet 30 mg tablet Quantity for one Quantity
for one Ingredients tablet in mg (wt %) tablet in mg (wt %)
Ulipristal acetate 10.00 (10) 30.00 (10) Lactose Monohydrate 79.00
(79) 246.00 (82) Povidone 5.00 (5) 9.00 (3) Croscarmellose sodium
5.00 (5) 12.00 (4) Magnesium stearate 1.00 (1) 3.00 (1) Total
100.00 (100) 300.00 (100)
[0059] The subject may provided with a kit comprising i) a dosage
form, preferably an oral dosage form such as a tablet, comprising
ulipristal acetate and ii) a printed matter stating that ulipristal
acetate is more efficient than levonorgestrel in providing post
coital contraception when the subject is overweight or obese,
compared to a non-overweight or non-obese subject.
[0060] Preferably the dosage form comprises 30 mg ulipristal
acetate.
[0061] Such printed matter serves as a labelling for the
medicament. For instance it is conveniently a leaflet inserted into
the packaging of the medicament, or it may be the packaging itself,
on which the information is printed.
[0062] The FIGURE and example illustrate the invention without
limiting its scope.
EXAMPLE
Example 1
Effect of BMI on Pregnancy Rates
[0063] 1.1. Phase II protocol
[0064] This Phase II, prospective, multicenter, randomized,
double-blind study was performed to compare the efficacy of a
single 50 mg dose of ulipristal acetate (unmicronized in gelatine
capsule) with two 0.75 mg doses of levonorgestrel used as an
emergency postcoital contraceptive within 72 hours of unprotected
intercourse. The study was carried out in seven sites in seven
different states in the United States.
[0065] Women (aged.gtoreq.18 years old) not using hormonal
contraception and who requested emergency contraception within 72
hours (3 days) after unprotected coitus defined by lack of
contraceptive use, condom breakage or other barrier contraceptive
method failure were included. Subjects were required to have a
history of regular menstrual cycles (mean length of 24-42 days with
intra-individual variation of .+-.5 days). At least one normal
menstrual cycle (two menses) was required after delivery, abortion,
or discontinuation of hormonal contraception. Subjects were
excluded from the study if they were pregnant at screening or
enrolment (assessed by a high-sensitivity urine pregnancy test),
pregnant or breastfeeding within the 2 months before screening,
using an intra-uterine device (IUD) or female or male sterilization
as a contraceptive method, uncertain about the date of the last
menstrual period (.+-.3 days), had been nauseated or vomited in the
2 weeks before screening, had used oral glucocorticoid replacement
therapy in the year before the screening, or were currently
enrolled in any other investigational trial.
[0066] Each woman returned for a follow-up visit 5 to 7 days after
the expected onset of her next menstrual period and a
high-sensitivity urine pregnancy test was performed. The primary
objective was to compare the efficacy, as determined by pregnancy
prevention, of 50 mg ulipristal acetate and levonorgestrel used as
an emergency postcoital contraceptive within 72 hours of
unprotected intercourse.
[0067] As defined in the protocol, the primary analysis was
performed on the modified intent-to-treat (mITT) population, which
included all subjects randomized, who had received at least one
dose of the study treatment and had a post-treatment pregnancy
evaluation.
1.2. Phase III protocol
[0068] This was a prospective, single-blind (subject and sponsor
blind, investigator not blind), randomized, multicenter, 2-arm
parallel comparative study designed to evaluate the efficacy,
safety and tolerability of a single dose of ulipristal acetate (30
mg) compared to levonorgestrel (1.5 mg) administered for EC within
120 hours after unprotected intercourse. It was performed in 10
centers in Europe and 25 centers in the US.
[0069] Women (aged 16 years), with regular menstrual cycles
(between 24 and 35 days and intra-individual variations less than
or equal to 5 days), who presented for EC within 120 hours after
unprotected intercourse at a participating study site and who met
the inclusion/exclusion criteria were enrolled into the study after
they signed informed consent form. Subjects were excluded from the
study in case of ongoing pregnancy or breast-feeding or current use
of hormonal contraception or IUD.
[0070] The study medication (ulipristal acetate 30 mg or
levonorgestrel 1.5 mg) was administered according to a random
allocation procedure generated electronically. Treatment was
administered orally immediately after all eligibility criteria
(including negative urine pregnancy test) had been verified. At the
first follow-up visit (5-7 days after expected onset of menses), a
subject was determined to be not pregnant if she had a negative
urine pregnancy test and menses had occurred, or was determined to
be pregnant if she had a positive pregnancy test confirmed by serum
.beta.-hCG; the subject was then considered pregnant and the second
follow-up (12-14 days after onset of expected menses) visit was
omitted. If at the second follow-up visit, a subject still had a
negative urine pregnancy test but menses had not occurred, a serum
.beta.-hCG test was performed.
[0071] The primary objective of the study was to provide evidence
that the pregnancy rate observed after taking ulipristal acetate
(30 mg) within 72 hours of unprotected intercourse is lower than
the expected pregnancy rate in the absence of EC.
[0072] The efficacy analysis was performed on the modified Intent
To Treat (mITT) population which included all subjects who had
received study drug, were participating in the study for the first
time (multiple enrolments were allowed in the protocol), had a
known pregnancy status after emergency contraception intake, were
aged up to and including 35 years, and did not have a pregnancy
identified as having started before ulipristal acetate intake or
not compatible with study drug failure, based on independent
evaluation.
[0073] In order to ensure unbiased evaluation of pregnancy data, an
independent, autonomous DSMB composed of two experts in the field
of gynecology, one methodologist and one expert in ethical
questions was established to review incidence of pregnancy with
respect to unacceptability threshold and give recommendations
during the course of the clinical trial. In addition, the DSMB
assessed whether each pregnancy was "compatible" or "not
compatible" with treatment failure based on available data.
1.3. Meta-Analysis
[0074] The effect of BMI was assessed by comparing pregnancy rates
among sub-groups of the study populations according to common BMI
categories. Pregnancy rates increased starting from BMI>25, and
for women with a BMI>30 the 95% CI of the observed pregnancy
rate overlapped with the expected pregnancy rate. However, the
differences between different BMI classes did not reach statistical
significance.
[0075] In the logistic regression model used to compare ulipristal
acetate and levonorgestrel in the meta-analysis, BMI was found to
be a significant predicting factor of pregnancy, regardless of the
treatment group (p<0.0001). When the efficacy of ulipristal
acetate and levonorgestrel arc then compared following
stratification of the population according to World Health
Organization BMI classes: underweight (<18.5), normal weight
(18.5 to 24.99), overweight (25 to 29.99), obese grade I (30 to
34.99), obese grade II (35 to 39.99), obese grade III and more
(.gtoreq.40), differential efficacy is observed. Results are
presented in Table 3.
TABLE-US-00003 TABLE 3 Pregnancy rate by WHO BMI class (ulipristal
acetate and levonorgestrel) Pregnancy rate BMI class (WHO) N
Ulipristal acetate Levonorgestrel Underweight 145 0 1.43% Normal
weight 2087 1.16% 1.33% Overweight 744 1.06% 2.45% Obese grade I
285 1.47% 6.71% Obese grade II 107 3.64% 3.85% Obese grade III 77
5.56% 4.88%
[0076] BMI classes were grouped: underweight+normal weight,
overweight and obese grade 1 and obese grade II and III. Pregnancy
rates in these pooled BMI classes are displayed below (Table 4),
and are shown on the FIGURE.
TABLE-US-00004 TABLE 4 Pregnancy rate by grouped BMI class
(ulipristal acetate and levonorgestrel) Pregnancy Rate Odds BMI
Class Ulipristal Ratio (WHO) N acetate Levonorgestrel [95% CI]
p-value Underweight & 2232 1.08% 1.34% 0.81 NS Normal [0.37;
1.73] Overweight & 1029 1.17% 3.68% 0.31 p = Obese I [0.11;
0.0073 0.74] Obese II and 184 4.40% 4.30% 1.02 NS more [0.23;
4.44]
[0077] For women overweight or with grade I obesity (BMI
[25-34.99]), the risk of pregnancy is divided by 3 when taking
ulipristal acetate versus levonorgestrel and this is highly
statistically significant (p=0.0073).
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