An open-label, randomized, two-period, two-sequence crossover, single-center trial to assess the bioequivalence of a single dose of 600 IU of freeze-dried r-hLH (Luveris®) versus a single 600 IU dose of the liquid formulation of Luveris® in the Pre-Filled Pen, administered subcutaneously (SC) in pituitary suppressed healthy premenopausal female subjects.

Liquid Luveris® is a new formulation of the already registered Luveris®.
Luveris® is a genetic engineered and therefore named recombinant version of the
natural hormone that stimulates ovulation in women (LH: luteinizing hormone)
and may be useful in helping women who have problems to get pregnant.
The formulation of Luveris® that is already registered is a freeze-dried (FD)
form, a powder that has to be dissolved in water prior to injection. The liquid
formulation of Luveris® does not require adding water and can be injected with
a ready to use pen (Pre-Filled Pen).
The liquid Luveris® is not registered as a drug but has been administered to
humans before.

Primary:
to assess the bioequivalence of LH after administration of the freeze-dried
(FD) Luveris formulation (Reference) versus the liquid formulation of Luveris
in the pre-filled pen (Test) based on the PK parameters AUC0-t and Cmax of
serum LH.

Secondary:
to assess the safety and tolerability of FD Luveris and liquid Luveris
administered in the pre-filled pen
to compare the local tolerability of FD Luveris and liquid Luveris administered
in the pre-filled pen

A phase I, open-label, randomized, two-period, two-sequence crossover, single
center, bioequivalence study with 54 healthy premenopausal female subjects;
subjects will be switched from their own combined oral contraceptive pill
(COCP) to Marvelon®; eligibility will be checked after 17 days of Marvelon®; if
eligibility is confirmed than subjects will be randomized to receive a single
subcutaneous dose of FD Luveris® in one period and a dose with liquid Luveris®
in the pre-filled pen in the other period, with a wash-out of fourteen days
between dosing

Procedures and assessments:
Screening: Demographics, medical history, history of medication, physical
examination (including gynecological exam), drug and alcohol screen, vital
signs (including blood pressure, heart rate and temperature), 12-lead ECG,
clinical laboratory, pregnancy test, LH/FSH/E2, testosterone, TVUS, adverse
events and concomitant medication
Repeated at day of admission on each period: drug and alcohol screen, clinical
laboratory, pregnancy test, LH/ E2, TVUS, adverse events and concomitant
medication
Follow-up: physical examination (including gynecological exam), vital signs
(including blood pressure, heart rate and temperature), 12-lead ECG, clinical
laboratory, pregnancy test, LH/FSH/E2, TVUS, adverse events and concomitant
medication

Blood sampling:
for pharmacokinetics of LH: pre-dose until144 h post-dose on Days 1 and 15.

Safety assessments:
adverse events and diary card check: throughout the study.
vital signs and 12-lead ECG: pre-dose on Days 1 and 15.
local tolerability: until 24 h post-dose on Days 1 and 15.

Test treatment:
a single dose of four clicks with the fertility pen of 150 IU Luveris each,
administered immediately after each other

Reference treatment:
a single dose of four subcutaneous injections of 150 IU Luveris each ,
administered immediately after each other

During the cervical smear and TVUS, subjects may experience discomfort from the
pressure applied when the speculum (an instrument used to hold the vagina open)
is inserted into the vagina or when the cervix is scraped to take a cervical
smear. Subjects may experience temporary spotting or bleeding after a cervical
smear is performed. The TVUS is usually painless and the level of discomfort
is similar or less than a normal gynecological examination.

Luveris® has been well tolerated in previous clinical studies. Common possible
side effects are injection site reactions (e.g. pain, redness, swelling,
irritation) and headaches, nausea, vomiting, diarrhea, abdominal pain.
Very rarely there may be mild to severe allergic reactions seen.
The following more severe side-effects of Luveris may occur, however in
particular when Luveris® is administered concurrently with Follicle Stimulating
Hormone (FSH) in the treatment of infertility. In the present drug study in
which no FSH will be administered and Marvelon will be taken these side-effects
are unlikely: ovarian hyperstimulation (sometimes leading to ovarian
enlargement), ovarian cysts. Ovarian hyperstimulation can further cause a
potentially life threatening condition called ovarian hyperstimulation syndrome
(OHSS). This condition is characterized by severe pelvic pain, swelling of the
legs and hands, stomach swelling and dyspnea. Blood clots associated with
ovarian hyperstimulation syndrome (when used with some hormonal therapies) have
also been seen.

Common minor symptoms of Marvelon® include nausea, breast tenderness, fluid
retention, and depression. Some women experience increases in blood pressure
and thrombosis can occur.

Registration af adverse effects: During the entire investigation all adverse
effects will be documented.

Blood draw, indwelling canula: During this study approximately 260 ml of blood
will be drawn. On Day -1 and Day 14 an indwelling cannula will be inserted for
blood sampling on Days 1, 2 and Days 15, 16. On the other days during this
study, blood will be drawn by direct puncture of the vein.

Heart trace (ECG*s): ECG*s will be made regularly.

Gynecological examination: A gynecological examination including physical
examination of the breast will be performed at screening and at the follow up
visit.
Cervical Smear: At screening a cervical smear test will be performed.
Transvaginal Ultrasound (TVUS): This examination will take place at screening,
at the follow-up visit and up to approximately 48 hours before dosing in each
period.