PK/PD trial with different dose regimens of Cyclogest® in comparison to Crinone® and placebo in healthy female subjects

Cyclogest Pessaries® are currently developed for the indication of progesterone
supplementation as part of an Assisted Reproductive Technology ("ART")
treatment for infertile couples. Other products have been developed for this
indication but in this study Crinone 8% gel will be the active comparator.
Clinicians suggest that Crinone® is dosed too low as they observe more bleeding
after this treatment than after Cyclogest®. Crinone® (Merck-Serono) claims to
have a sustained release profile with the capability of sticking to the vaginal
mucosa.

The sponsor intends to develop Cyclogest® for luteal phase support in women
having undergone IVF. It has been requested from MHRA in a Scientific Advice
meeting to justify a dose and the duration of treatment before performing a
non-inferiority trial in patients with this new indication.

The aim of this trial is to gain information about various dose strengths of
Cyclogest® and to collect reliable data with special regard to the
pharmacodynamic effect on the endometrium that would allow to design a clinical
non-inferiority trial with less patients and/or less risk of failure.

To investigate the effect of various dose regimens of Cyclogest® on secretory
transformation of the endometrium in comparison to Crinone® and placebo

To investigate single and multiple dose pharmacokinetics of Cyclogest®

To investigate safety and tolerability of single and multiple doses of
Cyclogest®

This is a randomized, single-center observer blind trial including two parts,
one consisting of a 3-way crossover (Part 1), and the other consisting of 3
study periods with a 2-way crossover performed in periods 1 and 2 followed by a
placebo control in period 3 (Part 2).

Part 1 will be a 3-way crossover with multiple dose application over 10 days of
200 mg Cyclogest® bid, 400 mg Cyclogest® bid, and 90 mg Crinone® od.

Part 2 will consist of a 2-way crossover with multiple dose application over 10
days of 100 mg Cyclogest® bid, 100 mg or 200 mg or 400 mg od followed by
placebo treatment (2 times daily application). The dose regimens to be
administered (100 mg or 200 mg or 400 mg od) will be defined after the PD
results were obtained from Part 1 (after 42 subjects completed period 1).

Taking into account replacement of dropouts, it is estimated that approximately
96 subjects will have to be included into the study in order to obtain 84
evaluable subjects. Subjects who drop out before the end of the second
treatment epriod will be replaced

The study treatment will consist of a screening and synchronization phase
(about 1 to 42 days) followed by three periods of study drug administration
over 24 days and 4 treatment / pill free days.

During each treatment period, E2 will be taken orally by the subjects for 24
days (Day 1 to Day 24). The study drug (progesterone or placebo) will be
administered concomitantly on Day 15 to 24. Then subjects will have a treatment
free period of 4 days (Days 25 to 28), followed by a washout phase of at least
17 days of COC intake followed by 4 pill free days. This wash-out cycle can be
repeated according to subject*s feasibility of participating in the next
treatment period. After completion of the last treatment period, subjects will
have a follow-up visit 16 ±2 days after last application of vaginal study drug

Cyclogest® pessary, vaginal administration: menstruation may occur earlier than
expected, or, more rarely, menstruation may be delayed. As with other vaginal
and rectal preparations, some leakage of the pessary base may occur. There is a
wide margin of safety with Cyclogest® pessaries but overdose may produce
euphoria and dysmenorrhoea.

Crinone® 8% gel, common side effects are: headache, sleepiness, breast
tenderness or vaginal irritation/itching/burning. Side effects reported after
marketing: intermenstrual bleeding (spotting), hypersensitivity reactions
usually manifesting as skin rash, and other mild application site reactions.
Rare events of urticaria and pruritus were noted.

Sleepiness might affect the ability to drive

Baseline treatments

Progynova®, The following undesirable effects have been reported during the use
of Progynova® as hormone replacement therapy for peri- and postmenopausal women
or for prevention of osteoporosis: hypersensitivity reaction, worsening of
hereditary angioedema (skin disease), worsening of porphyria (enzyme disorder),
increased or decreased weight, increased appetite, decreased glucose (sugar)
tolerance, anxiety/depressive symptoms, decreased or increased libido,
migraine, headache, dizziness, fatigue, chorea (nerve disease), stroke, visual
disturbances, intolerance to contact lenses, palpitations, myocardial
infarction, hypertension, thrombophlebitis (vein infection with blood clots),
venous thromboembolism (blood clot in vein or lung artery), nose bleed,
dyspepsia (disturbed digestion), abdominal pain, vomiting, nausea, bloating,
flatulence, gall bladder disease including gallstones, rashes, various skin
disorders (including itching, eczema, urticaria, acne, excessive body hair
growth, hair loss, erythema nodosum (skin rash with painful blue-red nodules),
erythema multiforme (skin rash, may be associated with nodules, vesicles, or
fluid retention), hemorrhagic rash, chloasma (yellow-brown pigment spots,
especially in the face), leg pain, cystitis-like symptom, increased size of
uterine fibroids, vaginal candidosis, uterine cervical erosions, changes in
vaginal bleeding pattern and abnormal bleeding or flow, breakthrough bleeding,
spotting, dysmenorrhoea, changes in vaginal secretion, premenstrual-like
syndrome, breast secretion, breast tenderness, enlargement or pain, oedema,
breast cancer, endometrial cancer.*

Microgynon® 30, Common side effects are: nausea, abdominal pain, weight
increase, headache, depressed mood, altered mood, breast pain, breast
tenderness. Uncommon side effects are: vomiting, diarrhoea, fluid retention,
migraine, decreased libido, breast growth, rash, urticaria. Rare side effects
are: contact lens intolerance, hypersensitivity, decreased weight, increased
libido, vaginal discharge, breast discharge, erythema nodosum (skin rash with
painful blue-red nodules), erythema multiforme (skin rash, may be associated
with nodules, vesicles, or fluid retention). Side effects reported after
marketing are: worsening of hereditary angioedema (skin disease),
hypertriglyceridemia (elevated blood triglyceride (lipid) levels), worsening of
chorea (nerve disease), Crohn*s disease, ulcerative colitis (chronic bowel
infections), liver function disturbances, reduced menstrual flow, spotting,
breakthrough bleeding and missed withdrawal bleeding, absence of bleeding after
stopping pill intake, chloasma (yellow-brown pigment spots, especially in the
face).

The following serious adverse events have been reported in women using combined
oral contraceptives: venous thromboembolic disorders (deep venous thrombosis
and lung embolia which means blood clot in vein or in lung artery), arterial
thromboembolic disorders (blood clot in artery), strokes (e.g. TIA (temporary
loss of a part of the brain function), ischemic stroke (brain infarction),
haemorrhagic stroke (bleeding in the brain)), hypertension, liver tumors
(benign and malignant).

The following conditions are reported to deteriorate with pregnancy or previous
COC use: jaundice and/or pruritus related to cholestasis; gallstone formation,
systemic lupus erythematosus (immune disease); herpes gestationis (herpes
during pregnancy); otosclerosis-related hearing loss (ear disease); sickle cell
anaemia; renal dysfunction; hereditary angioedema (skin disease); porphyria
(enzyme disorder); cervical cancer.

Changes in carbohydrate metabolism have been reported in women using combined
oral contraceptives.

Provera®, the following medical events have been occasionally to rarely
reported in relation to the use of progestogens like Provera®: hypersensitivity
reactions, e.g. anaphylaxis and anaphylactoid reactions (general allergic
reactions) and angioedema (swelling), weight change, oedema/fluid retention,
depression, sleeplessness, nervousness, dizziness, headache, sleepiness,
thromboembolic disorders (blood clot in artery or vein), nausea, acne, alopecia
(baldness), hirsutism (excessive body hair growth), itching, rash, urticaria,
breast secretion, breast tenderness, breast pain, tiredness, decreased glucose
(sugar) tolerance.

General, Generally, side effects of the investigational medication that have
been unknown so far must always be expected. If during this study more
information becomes available about this study medication, especially when this
can affect the readiness to participate, the subjects will be informed.

The frequency of diagnosis of breast cancer is slightly increased among users
of oral contraceptives and among women using hormonal preparations after
menopause. As breast cancer is rare in women under 40 years of age, the extra
risk to develop cancer is small in relation to the overall risk of breast
cancer. It is unknown if combined oral contraceptive use can cause breast
cancer.

A blood withdrawal or insertion of the cannula for blood sampling might be
painful or the subject may become temporarily dizzy. Furthermore, the subject
may experience intermittent complaints like re-bleeding or puncture site
bruise, blot clot in the punctured vessel (rarely), puncture site infections
(rarely) or mechanical nerve damage (very rarely).

Taking a biopsy of the lining of the subjects uterus may be painful during the
several seconds the procedure takes. Cramping and lower abdominal pain may
occur for minutes to hours afterwards. A painkiller is recommended to be used
before the biopsy to prevent or relieve the pain. The subjecy may experience
some light vaginal bleeding for a day or two. Very rarely, the procedure may
result in perforation of the uterus or infection which may require
hospitalization to treat.