A multicenter, randomized, partially blinded, placebo-controlled clinical trial to evaluate the effect on primary dysmenorrheal of vaginal rings with an average daily release of 700 µg nomegestrol acetate (NOMAC) and 300 µg estradiol (E2), or 900 µg nomegestrol acetate (NOMAC) and 300 µg estradiol (E2), or 100 µg etonogestrel (ENG) and 300 µg E2, or 125 µg etonogestrel (ENG) and 300 µg E2

NOMAC-E2
The NOMAC-E2 vaginal ring is being studied by Merck to evaluate its efficacy as
a contraception method. The vaginal ring is a combined contraceptive vaginal
ring that contains the progestogen nomegestrol acetate (NOMAC) and 17-beta
estradiol (E2). NOMAC alone (as Lutenyl® 5 mg, and Lutenyl® 3.75 mg) and NOMAC
in combination with E2 (as Naemis® 3.75 mg + 1.5 mg) have been approved in the
field of hormonal replacement therapy (HRT) for pre- and post-menopausal women.
Estradiol is a sex hormone, which is the same as the naturally produced
estrogen in females. Estradiol is an approved drug for the treatment of hot
flashes and other symptoms of menopause. In addition, both NOMAC and estradiol
are components of an approved oral contraceptive (Zoely® / IOA®).

As of May 2012, NOMAC-E2 in the form of a vaginal ring has been used by 71
female subjects between the ages of 18-45 in clinical trials. Multiple doses
of NOMAC ranging from 900 micrograms (µg) to 2000 µg per day, and E2 ranging
from 50 µg to 300 µg per day, have been administered in these studies to
healthy female subjects without safety concern.

ENG-E2
The ENG-E2 vaginal ring is being studied by Merck to evaluate its efficacy as a
contraception method. The vaginal ring contains etonogestrel (ENG) and 17-beta
estradiol (E2). ENG is a synthetic sex hormone which is a component of several
approved drugs for contraception. E2 is a sex hormone, which is the same as the
naturally produced estrogen in females. E2 is an approved drug for the
treatment of hot flashes and other symptoms of menopause. In addition, E2 is a
component of an approved oral contraceptive.

As of April 2012, ENG-E2 in the form of a vaginal ring has been used by 15
female subjects between the ages of 18-45 in a clinical trial. Subjects were
administered ENG 120 micrograms (µg) per day with E2 200 µg per day without
safety concern.

To identify at least one New Generation Ring that shows clinically relevant
treatment efficacy:
• in relief of primary dysmenorrhea, as demonstrated by a statistically
significantly larger reduction (as compared to baseline) in the mean menstrual
cramping pain score compared to placebo.
The trial will be considered a success if at least one treatment meets the
primary objective.

This is a randomized, placebo-controlled, multicenter, partially-blinded trial
of vaginal rings with an average daily release of 700 µg nomegestrol acetate
(NOMAC) and 300 µg estradiol (E2), or 900 µg nomegestrol acetate (NOMAC) and
300 µg estradiol (E2), or 100 µg etonogestrel (ENG) and 300 µg E2, or 125 µg
etonogestrel (ENG) and 300 µg E2 in female subjects with primary dysmenorrhea.

The trial design is appropriate for the indication studied. Validated methods
of data collection, analysis, and evaluation will be used for the trial.

Each subject will participate in the trial for approximately 5 months from the
time the subject signs the Informed Consent Form (ICF) at the beginning of the
screening visit through the final study visit. After completion of a baseline,
spontaneous, untreated, menstrual cycle, bounded on each end of the cycle by a
spontaneous menstruation, during the screening period, each subject will
receive assigned treatment for approximately 56 days (two 28-day treatment
cycles). After the end of treatment, each subject will be followed for safety
monitoring for at least 14 days at which time a final study visit (Visit 5)
will be conducted.

The nomegestrol acetate (NOMAC) contraceptive vaginal ring (NOMAC-E2-CVR) is an
all-EVA (ethylene vinyl acetate) vaginal ring containing estradiol (E2) with an
average daily release of 700 µg NOMAC and 300 µg E2, or 900 µg NOMAC and 300 µg
E2.

The etonogestrel (ENG) containing contraceptive vaginal ring (ENG-E2-CVR) is
also an all-EVA vaginal ring containing E2 with an average daily release of 100
µg ENG and 300 µg E2, or 125 µg ENG and 300 µg E2.

The placebo vaginal ring (PBO-CVR) is an all-EVA vaginal ring with no active
ingredients.

Each Investigational Medicinal Product (IMP) (NOMAC-E2, ENG-E2, or Placebo)
will be administered for two 28-day periods, each period (treatment cycle)
consisting of 21 days of vaginal ring use followed by 7 day vaginal ring-free
days.

ENG-E2
The overall benefits and risks of combined hormonal contraceptives, including
NuvaRing® and Zoely®, also apply to the ENG-E2 vaginal ring. Thus, the general
COC contraindications as well as the warnings and precautions in the Summary of
Product Characteristics are applicable. These warnings concern amongst others
the risk of circulatory disorders (VTE), and breast, cervical, and liver
tumors. If a woman has any of the following conditions, she may not be able to
place the ENG-E2 vaginal ring correctly or may lose the ring: prolapse of the
uterine cervix, cystocele and/or rectocele, or severe or chronic constipation.
ENG is the component primarily responsible for ovulation inhibition. The
simultaneous administration of EE with ENG in NuvaRing® induces increased SHBG
concentrations, which in turn decrease the serum levels of unbound
(bioavailable) ENG. Sex Hormone Binding Globulin-induction by E2 is much less
and therefore bioavailable ENG serum levels are expected to be higher when
using the ENG-E2 vaginal ring. Consequently, the contraceptive action of the
ENG-E2 vaginal ring is considered adequate.

NOMAC-E2
The overall benefits and risks of combined hormonal contraceptives, including
the NOMAC-E2 oral contraceptive and NuvaRing®, apply to the NOMAC-E2 vaginal
ring. Thus, the general COC contraindications as well as the warnings and
precautions in the Summary of Product Characteristics are applicable. These
warnings concern amongst others the risk of circulatory disorders (VTE), and
breast, cervical, and liver tumors. If a woman has any of the following
conditions, she may not be able to place the NOMAC-E2 vaginal ring correctly or
may lose the ring: prolapse of the uterine cervix, cystocele and/or rectocele,
or severe or chronic constipation.

NOMAC is the component primarily responsible for ovulation inhibition. Based
on data obtained in the previous NOMAC-E2 vaginal ring study (P307001) the dose
of NOMAC (900 µg/day) is considered to be sufficient for ovarian suppression.
Additional studies are planned to evaluate contraceptive efficacy. To date, no
efficacy studies have been performed with the NOMAC-E2 vaginal ring
formulations, therefore contraceptive efficacy can not yet be claimed and
subjects should use adequate barrier contraception, such as condoms during the
study.

General
NuvaRing® has no adverse effects on the cervix, vagina, and the endometrium,
nor did NuvaRing® adversely affect bone mass.

Restoration of fertility is expected to occur rapidly after discontinuation of
the NOMAC-E2 vaginal ring, based on the experience with NuvaRing® and NOMAC-E2
containing contraceptives.

Interaction studies with NuvaRing® showed that vaginally administered
antimycotics, spermicides, and broad-spectrum antibiotics do not jeopardize the
contraceptive efficacy and safety of NuvaRing® and the use of tampons does not
affect the concentration of hormones released by NuvaRing®. It is expected that
this will also be applicable to the ENG-E2 and NOMAC-E2 vaginal ring. In order
to rule out any possible interaction, no concomitant use of these medications
was/is allowed for the completed Study 07931 or for the planned studies.